Field of the Invention

The present invention relates to the fields of pharmaceutical sciences and process engineering which provides novel self-emulsifying amorphous solid dispersion resulting in pharmaceutical compositions with enhanced solubility and thereby enhanced bioavailability. The invention relates to an oral quick release composition of BCS Class IV drug substance and specifically that of an anti-HIV molecule. More particularly, the invention relates to a quick release composition of Etravirine which is BCS class IV drug having very low solubility as well as low permeability resulting into poor oral bioavailability. More particularly, invention relates to Solvent Free Solid Oral Composition of Etravirine.

These quick release compositions include tablets and capsules, fast disintegrating tablets, powder for oral suspension, or any composition which can be consumed with ease without difficulty in swallowing to overcome issue of “pill burden” or dysphagia, commonly associated with large size tablets and where patient is not losing the therapeutic dose. Further, these compositions are prepared by a process which does not require large amounts of solvents, particularly organic solvents. More particularly, these compositions are Solvent free compositions or green Pharmaceuticals which are effective for end user and safe for environment.

Objects of the Invention

A first object of the present invention is to provide a quick releasing compositions of BCS class IV drugs having low Solubility and low permeability which ultimately has bioavailability challenge. Such compositions should release active substance quickly and thereby enhance bioavailability. Such compositions include fast disintegrating compositions, powder for oral suspensions which can be reconstituted before administration, or ready to drink suspension etc. Second object of the invention is to provide Etravirine compositions which are less bulky and can be administered with ease, without difficulty in swallowing to overcome issue of “pill burden” or dysphagia, commonly associated with large size tablets.

Third object of the invention is to provide cost effective etravirine compositions and continuous process with minimum handling losses.

Fourth object of the invention is to provide Solvent free compositions of BCS Class IV drugs, where use of large amount of solvent can be avoided and disposal of such amounts of solvent(s) is not needed.

Yet another objective of the present composition is to provide highly bioavailable composition for Etravirine, which can attribute to lower dosage amount and frequency, despite compromising therapeutic efficacy.

One more object of the invention is to provide simple, robust and reproducible process to arrive at compositions which are faster and easier including same for Etravirine and other BCS Class IV drug substance, particularly.

Background of The Invention

Etravirine is marketed worldwide as an oral tablet. It was first disclosed in U.S. Pat. No. 7037917 as one of the Formula I-a compounds. This patent discloses that oral or rectal administration comprise particles obtainable by melt-extruding a mixture comprising a compound of formula (I-a)

(1-a) and an appropriate water-soluble polymer and subsequently milling said melt- extruded mixture. Said particles can then be formulated by conventional techniques into pharmaceutical dosage forms such as tablets and capsules. However, this patent does not mention the melting point of compounds of formula (I-a) and whether such melting is possible at the melting point of the compounds of formula (I-a).

US20150086628A1 discloses a pharmaceutical solid oral sprinkle composition, comprising a plurality of particles, the plurality of particles comprising a first and a second antiretroviral drug and at least one polymer, wherein the first antiretroviral drug comprises ritonavir. The second antiretroviral drug comprises a nonnucleoside reverse transcriptase inhibitor selected from nevirapine; rilpiverine; delaviridine; efavirenz; etravirine. Paragraph [0015] discloses a process for preparing a pharmaceutical solid oral sprinkle composition comprising one or more antiretroviral drugs, such as ritonavir, the process comprising melt extruding comprising the steps: (a) preparing a homogeneous melt of the one or more antiretroviral drugs; a polymer comprising: a water soluble polymer; a water swellable polymer; a water insoluble polymer; or any combination thereof, and optionally one or more excipients; (b) cooling the melt obtained in step (a); (c) allowing the cooled melt to solidify to obtain an extrudate; and (d) processing the extrudate into a desired shape. Ritonavir has a lower melting point of 126-132°C and moreover, it does not degrade if melted during hot melt extrusion. In hot melt extrusion method described under this patent application, a temperature exceeding melting point of Ritonavir has been reported. Such methods are not suitable for Etravirine.

US20180250271A1 discloses a pharmaceutical composition comprises at least one integrase inhibitor or its salt, solvate, complex, hydrate, isomer, ester, tautomer, anhydrate, enantiomer, polymorph or prodrug and at least one antiretroviral or antiHIV agent or its salt, solvate, complex, hydrate, isomer, ester, tautomer, anhydrate, enantiomer, polymorph or prodrug. There is also provided a hot melt extruded pharmaceutical composition comprising antiretroviral drug(s), for example at least one integrase inhibitor and at least one antiretroviral agent or anti-HIV agent as described previously, and at least one water soluble and/or water swellable and/or water insoluble polymer or combination thereof and optionally one or more pharmaceutically acceptable excipients. All examples of this patent application include dry granulation or compaction method for preparing granules of antiretroviral or anti-HIV agent. Hot melt extruded formulation is covered under claims without any mention or support in the specification. This patent application has not uncovered underlying problem of BCS class IV compounds such as Etravirine which is their insoluble nature. Hence there is no discussion on insoluble nature and conversion into a soluble form. In fact by adopting compaction, the process will not help in solubilizing insoluble compounds like BCS class IV drugs such as Etravirine.

An oral dosage form of a pharmaceutical agent majorly has the efficacy issue resulted because of bioavailability observed after oral administration of the dosage form. Various factors can affect the bioavailability of a drug when administered orally. These factors include aqueous solubility, drug absorption throughout the gastrointestinal tract, dosage strength, and first pass effect. Aqueous solubility is one of the most important of these factors. When a drug has poor aqueous solubility, formulator must make an attempt to make it soluble and thereby more bioavailable by adopting suitable dosage form and process. The bioavailability of the aqueous oral solution formulation of a drug is then generally used as the standard or ideal bioavailability against which other oral dosage forms are measured. For a variety of reasons, including patient compliance and taste masking, a solid dosage form, such as a capsule or tablet, is usually preferred over a liquid dosage form. However, oral solid dosage forms of a drug generally provide a lower bioavailability than oral solutions of the drug. One goal of the development of a suitable solid dosage form is to obtain a bioavailability of the drug that is as close as possible to the ideal bioavailability demonstrated by the oral aqueous solution formulation of the drug and attempt to made patient friendly and dosage form, which is equally environment friendly.

For any drug substance to have therapeutic effectiveness, aqueous solubility and permeability across biological membranes are essential prerequisites after oral absorption. Around 70-90% of all new chemical entities (NCEs)/drug molecules under development were reported to possess poor aqueous solubility; hence, they belong to the Biopharmaceutics Classification System (BCS) class II or class IV drugs. This phenomenon of poor solubility is due to the structure and functional groups identified during the drug discovery phase. In an attempt to improve the poor solubility of NCEs, approaches such as modifying the structure-activity relationship (SAR) were tried during the preclinical development stage. However, the use of these approaches on NCEs is often limited, due to the requirement of a lipophilic nature to bind biological targets or to cross biological membranes. Therefore, this resulted in an increased number of poorly aqueous soluble NCEs in the preclinical development, posing a challenge during formulation development. Based on physicochemical properties such as melting point, logP, molecular weight and aqueous solubility, NCEs were classified as either ‘brick-dust’ molecules or ‘grease-ball’ molecules. The former name indicates solid-state limited solubility (due to orderly arranged crystalline lattices) and the latter denotes solvation-limited solubility (due to high lipophilicity). Therefore, as mentioned earlier, aqueous solubility and membrane permeability were found to be pivotal in the pipeline of successful formulation development.

Preparing compositions, particularly oral compositions for class IV molecules are extremely challenging because these molecules are neither soluble in physiological pH medium nor permeable through gastric mucosa.

Etravirine, also known as 4-(6-amino-5-bromo-2-(4-cyanophenylamino)pyrimidin- 4-yloxy)-3,5-dimethylbenzonitrile, inhibits reverse transcriptase by binding at a non-substrate site on the enzyme, different than that for nucleoside analog reverse transcriptase inhibitors (NRTIs) and nucleotide analog reverse transcriptase inhibitors (NtRTIs). Upon binding the enzyme at a site proximal to the polymerase active site, etravirine can inhibit the movement of protein domains that are needed to carry out the process of DNA synthesis.

Etravirine is currently approved for treatment of HIV-1 infection in combination with additional antiretroviral agents. Etravirine and largely similar BCS class IV drug substances, are insoluble in water and practically insoluble across the pH range of 1 - 6.8, which may result into poor bioavailability after oral administration. Several attempts have been made by researchers to enhance solubility and thereby bioavailability of Etravirine. One of the most successful attempts resort to spray drying process and employ “significantly” large amount of organic solvents to prepare spray dried form of Etravirine. .

Mikal Rekdal et al prepared cocrystals of Etravirine employing co-former tartaric acid. (Rekdal et al. ; 2018).

W02001023362 provides Etravirine (TMC 125) nicotinamide co-crystal, its preparation, and use in the treatment of HIV infection.

Solubility can be enhanced by converting crystalline Etravirine, a BCS Class IV drug, to amorphous form. The crystallinity of the drug can be altered to yield amorphous drug substance by dissolving in the suitable solvent. Most of the time, the solvents required are Class II or III solvents and are not suitable for the human consumption, if found above the permissible limit. Another less preferred option is melting with carriers. Melting is not always feasible, as most of the drugs and excipients may degrade at high temperatures. Further, more exposure to high temperature causes browning/charring and there is likelihood of increase in one or more impurities of such drug substance and even that of Etravirine.

Further, even solid dispersion will improve the solubility in aqueous physiological pH medium but not necessarily will modify the permeability.

Therefore, choosing a manufacturing process that will modify crystallinity without causing degradation of drug substance, is challenging. Spray drying offers one such option which helps to convert the drug into Amorphous form and also prevent degradation, but it employs large amounts of solvents to do so. The solvents are organic solvents from Class II or Class III and majority of the time, those are hazardous to end user, manufacturer and has impact on environment largely.

Traditional compositions resulted in no or very low blood plasma levels. WO 01/23362 and WO 01/22938 disclose solid dispersions of Etravirine in water- soluble polymers offering improved bio availability, especially when in the form of powders prepared by spray-drying. Intelence™ is available as tablets that contain a solid dispersion of Etravirine in HPMC obtained by spray-drying, using substantially large amounts of organic solvents, which are unsafe beside hazardous for environment around us. The current dosing regimen of etravirine is 200 mg twice a day (b.i.d.), administered as two tablets each containing 100 mg. to be taken in at once, preferably two in the morning and two at the end of the day. Because of these dosing requirements and the fact that etravirine is dispersed in a relatively large quantity of water-soluble polymer, dosage forms of this drug inevitably are large in size. This contributes to the so-called “pill-burden', a term that covers all inconveniences associated with the intake of drugs such as, for example, frequent daily dosing, specific administration requirements, e.g., before, during or after a meal, large dosage forms, or combinations of these factors. Large dosage forms can be problematic for patients having difficulty in Swallowing, such as children or the elderly. Frequent dosing and specific administration requirements put a heavy burden on patients not to forget taking their medication and to take it at the right time. All these factors contribute to the risk that patients will not take their entire dose, thereby failing to comply with the prescribed dosage regimen. Large dosage form often becomes point of rejection of therapy on continuous usage. This scenario is extremely common for majority of BCS Class II drugs and almost all BCS Class IV drugs and new chemical entities, and not limited to Etravirine.

Spray drying process often converts Etravirine into an amorphous fluffy composition, thereby increasing solubility of Etravirine. Spray dried Etravirine compositions are bulky although they enhance release of Etravirine. Dose of Amount of Etravirine contained in unit dosage form is reduced to less than 25 % in most cases or even less such as less than 20 % or even less than 15 %.

As a result of reduced content that is held in unit dosage form and bulky size, these compositions are unusually large when compared to dose they contain. For example, Intelence™ for accommodating 100 mg of dose, the composition has to be compressed using larger punches such as 19 mm. while Intelence™ for 200 mg of dose, a composition weights around 1400 - 1500 mg. This composition is compressed using larger punches such as 22.5 mm. A big and bulky tablet loses patient compliance. Additionally, for population who have problems like dysphagia and having difficulty in swallowing, it is recommended that such composition is dispersed in a little amount of water before ingestion. This further creates troubles for patients who need to travel or who are frequently on move etc.

Spray dried formulations are expensive. Production on large scale is time consuming. The production is both labour and cost intensive. Excessive use of organic solvents also necessitates proper disposal. When the entire world is looking at processes employing Green Chemistry. Such excessive use of solvents should be avoided.

Method of administration of Etravirine Marketed formulation Intelence™ is as provided below:

“Instruct patients to swallow the Intelence™ tablet(s) whole with liquid such as water. Patients who are unable to swallow the Intelence™ tablet! s) whole may disperse the tablet(s) in water. Instruct the patient to do the following: place the tablet(s) in 5 mL (1 teaspoon) of water, or at least enough liquid to cover the medication, stir well until the water looks milky, add approximately 15 mL (1 tablespoon) of liquid. Water may be used but other liquids, such as orange juice or milk, may improve taste. Patients should not place the tablets in orange juice or milk without first adding water. The use of warm (temperature greater than 104°F [greater than 40°C]) or carbonated beverages should be avoided, drink the mixture immediately, rinse the glass several times with orange juice, milk or water and completely swallow the rinse each time to make sure the patient takes the entire dose.”.

There are chances of not consuming accurate dose when such bulky tablets are dispersed in water taken on a spoon. Such suspension can be spilled out of the spoon while consuming.

There is a need for better accuracy, safety and patience compliance to provide alternate quick releasing compositions of Etravirine, applicable to other BCS class IV formulations, which are less bulky and can be consumed with ease and accuracy. There is also a need in the art to develop Solvent free, easy, economical processes for producing Etravirine compositions complying with Green Chemistry initiative.

One such process of manufacturing is using hot melt extrusion method. A solid dispersion obtained by solidifying a poorly water-soluble drug and a polymer through hot melt extrusion, contains the drug in an amorphous state and has the drug molecularly dispersed in the polymer carrier. Such a solid dispersion has notably increased apparent solubility and improved bioavailability. Since the hot melt extrusion can be carried out in the absence of a solvent, it is applicable to a drug which is unstable in water. Unnecessity for the solvent recovery in the hot melt extrusion has advantages of a safety, no environmental concerns, saving energy used for a solvent recovering step, and an improvement in a safety of the workers. Further, the hot melt extrusion enables continuous production, differing from the conventional batch production systems, and attracts attentions from the standpoint of productivity and energy consumption per hour.

However, there are several challenges in such methods particularly for high dose compositions characterized by poor flow. Hot melt extrusion being a continuous process and if the flow of blend from hopper to screw is not good, such material cannot be processed efficiently. Generally cohesive property of API imparts the poor flow and pose difficulty in processing. The poor blend issue needs to be resolved for smooth process and good yield, persistent. As majority of NCEs and BCS Class IV compounds are low in there native solubility, they usually synthesized in micronized form and thus, make poor in flowability.

Other parameters which can be impacted include tensile strength, hardness and disintegration time of tablets produced from granules prepared by hot melt extrusion. Further, there are chances that such granules have low compressibility and a high compression force may be needed.

Also, during melt granulation, torque can exceed beyond set limits and hence all process parameters should be closely monitored. Yet another challenge in using hot melt extrusion is degradation at high temperatures. Hot melt technique is more suited for thermostable molecules. Process temperature as well as residence time of the material are important factors that can influence stability of compositions.

Summary of the Invention

Under various aspects, the invention provides a process of preparation and a pharmaceutical composition of BCS class IV drugs wherein such process is partly a continuous process and the process and product are solvent free and complying with the requirements of green chemistry.

Under various aspects, the present invention is concerned with pharmaceutical compositions of BCS class IV compounds (Etravirine) which can be administered to a mammal, in particular a human, suffering from an HIV infection. These compositions comprise particles obtainable by melt-extruding a mixture of BCS class IV compound and one or more appropriate water-soluble polymers and one or more dispersing agents and optionally one or more flow aids and subsequently milling said melt-extruded mixture. Additionally, stabilizer can be added.

A solid dispersion comprises, in essentially non-crystalline form, an etravirine herein, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier and (b) a pharmaceutically acceptable plasticizer/dispersing agent. A process for preparing such a solid dispersion comprises subjecting to elevated temperature the BCS class IV compound, the water-soluble polymeric carrier and the plasticizers/dispersing agents, to provide an extrudable semi-solid mixture; extruding the semi-solid mixture; and cooling the resulting extrudate to provide a solid matrix comprising the polymeric carrier and the dispersing agent and having the compound dispersed in essentially noncrystalline form therein.

Under an aspect, the invention provides quick release compositions of BCS class IV drug including but not limited to, Etravirine and other similar compounds. These compositions are Self Emulsifying Amorphous Solid Dispersion / Solution which are for better ease of swallowing thereby reducing “pill burden”.

More particularly, invention relates to Solvent Free Solid Oral Composition of Etravirine, especially free of Organic Solvents .

Under various aspects, these compositions can be further developed into fast disintegrating tablets or powder for oral suspension, ready to drink suspension, or suitable oral composition or which can be administered with ease, without having difficulty in swallowing and thus ensuring complete and proper dosing.

According to one preferred aspect, current invention the Self-Emulsifying Amorphous Solid Dispersion / Solution is prepared from Etravirine, polymer and / or co-polymer and a suitable dispersing agent. Suitable dispersing agent in ternary mixture with Etravirine and polymer and / or co-polymer reduces / lowers down the processing temperature in hot melt extrusion as a result of reduction of the glass transition temperature of hydrophilic polymer.

Selection of polymer is crucial. Polymers having low glass transition temperature and highly miscible with the etravirine are ideal candidates to get amorphous dispersion at the temperature below the melting point of the etravirine.

Dispersing agent can also be a plasticizer or a solubilizer. Use of plasticizers is well known approach to reduce the glass transition temperature of the polymer. Thus, the selection of proper plasticizers/solubilizers is another key point in processing the etravirine at the temperature below the melting point.

Combining Etravirine, polymer and / or co-polymer and a suitable dispersing agent leads to generation of a glassy solid dispersion of etravirine enhancing solubility of etravirine.

The product and process of the present invention achieves all desired characteristics of product and process such as Enhanced solubility and bioavailability of Etravirine, Reduced Bulkiness, accurate dosing, ease of administration / consumption of Etravirine compositions, Solvent free, easy, economical process complying with Green Chemistry initiative. Brief Description of Drawings

Figure 1 provides comparative release profile of F064A and RLD 200 mg in the single-phase dissolution condition. Conclusion: Dissolution kinetics of test batch (F064A) was found to be faster than RLD at initial time points. Though the dissolution profile of test is like RLD, incomplete release was observed with the current composition.

Figure 2 provides comparative release profiles of test batches F077O and F079C RLD 200 mg in the single -phase dissolution condition

Conclusion: Addition of meglumine helped in preventing the etravirine degradation at higher processing temperature.

Figure 3 provides Comparative release profiles of test batches F064A and FO88D and RLD 200 mg in the single -phase dissolution condition Conclusions: Even the lower quantity of meglumine (when compared to F079C batch mentioned above)helped in the prevention of etravirine degradation during HME process and aided in enhancing the dissolution rate of etravirine.

Figure 4 provides Comparative release profiles of test batches FO88E and F094C and RLD 200 mg in the single -phase dissolution condition. Conclusions: In FO88E the initial rate is fast, but the dissolution rate decreases in later time points. Whereas incorporating HPMC led to an initial drop in the dissolution rate, but sustained release rate is achieved in the later time points.

Figure 5 provides Comparative release profiles of test batches F090A and F091A and RLD 200 mg in the single -phase dissolution condition.

Conclusions: The data showed the dissolution rate of etravirine is faster when processed with TPGS owing to its better dispersion property than PEG 3350.

Figure 6 provides Comparative release profiles of test batches F096D and F097C and RLD 200 mg in the single-phase dissolution condition. Conclusions: The data showed the dissolution rate of etravirine is faster when mixed Vivapharm PVP/VA 64. Figure 7 provides Comparative release profiles of test batches F100C and F107C and RLD 200 mg in the single -phase dissolution condition where both test batches exhibited faster release than RLD. Conclusions: Incorporating MCC/PVA helped in sustaining the supersaturation for longer period. PVA showed better sustainability than MCC.

Figure 8 provides Comparative release profile of F032E and RLD in the singlephase dissolution condition where test batch viz. F032E exhibits faster release profile at initial time points compared to release of RLD.

Figure 9 provides Comparative release profiles test batch and RLD in the singlephase dissolution condition where test batch viz. F035F has similar release profile as that of RLD.

Figure 10 provides Comparative release profiles of test batch and RLD in the singlephase dissolution condition wherein both test batches viz. F072C and F072D exhibited much faster release than RLD product.

Figure 11 provides Comparative release profiles test batch and RLD 200 mg in the single-phase dissolution condition wherein both test batches viz. F078D and F079D exhibited much faster release than RLD product.

Figure 12 provides Comparative release profiles of test batch and RLD in the singlephase dissolution condition. Conclusions: The ready to drink suspension batches showed faster release than the RLD . This quicker release is the outcome of the colloidal type of dispersion where the molecules are nano-amorphously dispersed within the suspension.

Figure 13 provides Comparative release profiles test batch and RLD 200 mg in the single-phase dissolution condition. Conclusions: The faster release of current HME formulation is expected to be supra-bioavailable than the existing RLD.

Figure 14: XRD diffractograms of (A) Pure Etravirine, (B)Extruded materials, and (C) Placebo. It is clearly seen that Etravirine crystalline form (A), pure Etravirine is completely converted to amorphous form in extruded material (B). Detailed Description of the Invention

Definitions

Unless defined otherwise, all the technical and scientific terms used herein have the same meanings as commonly known by a person skilled in the art. In case of conflict, the definitions provided herein will prevail. Unless specified otherwise, all the percentages, portions and ratios in the present invention are on weight basis.

The terms “about” and “approximate,” when used along with a numerical variable, generally means the value of the variable and all the values of the variable within a measurement or an experimental error (e.g., 95% confidence interval for the mean) or within a specified value (e.g., ±10%) within a broader range.

As used herein the term “Etravirine” refers to Etravirine free base or its pharmaceutically acceptable salts, co-crystals, solvates or hydrates thereof. In principle, any crystalline form of Etravirine or amorphous form of Etravirine may be used for manufacturing the pharmaceutical composition of the present invention. The term “pharmaceutically acceptable substances” means those, which, according to a person skilled in art of pharmaceutical / medical sciences, are suitable to be in contact with a tissue of a patient without any inappropriate toxicity, irritation, allergic response, etc., have a reasonable balance between advantages and disadvantages, and can be applied to its target use effectively.

The terms “pharmaceutical composition,” “pharmaceutical product,” “pharmaceutical dosage form,” “dosage form,” “pharmaceutical formulation,” etc., refer to a pharmaceutical composition administered to a patient in need of treatment, which is typically in the form of powder, granules, pill, beads, capsule, caplet, tablet, oral suspension etc.

The terms “carrier” and “pharmaceutically acceptable carrier” are interchangeable. The carrier is able to form a matrix embedding (surrounding) the active ingredient. The matrix may comprise one carrier or a mixture of two or more carriers. The carrier used in the solid dispersion of the present invention may be an enteric polymer or non-enteric polymer. The term “solubility” means solubility of Etravirine or its pharmaceutically acceptable salts in aqueous media such as water, buffer, gastrointestinal simulated fluid, gastrointestinal fluid and the like.

The term “in vivo” in general means in the living body of a plant or animal, whereas the term “in vitro” generally means outside the body and in an artificial environment.

As used herein, the term “reference formulation” or Reference Listed Drug or simply RLD product is a formulation that is used for comparison. Preferably, the reference formulation may refer to an oral dosage form containing 25 mg, 100 mg or 200 mg of Etravirine. Preferably, the reference formulation corresponds to an oral dosage form of Etravirine, which is currently marketed under the brand name Intelence™.

By “solid dispersion” is meant a molecular dispersion of a compound, particularly a drug substance within a carrier. The term solid dispersion in general means a system in solid state comprising at least two components, wherein one component is dispersed substantially evenly throughout the other component(s). For example, solid dispersions may be the dispersion of one or more active ingredients in an inert carrier or matrix at solid state, prepared by the melting, solvent, or melting -solvent methods. While not wishing to be bound by theory, in a solid dispersion, the drug may be present in a molecular state, colloidal state, metastable state, or an amorphous state. Formation of a molecular dispersion may provide a means of reducing the particle size to nearly molecular levels (i.e., there are no particles).

Solid dispersions, and, particularly, solid solutions, have been frequently employed to promote the oral bioavailability of poorly water soluble active pharmaceutical ingredients. The term “a solid dispersion' defines a system in a solid state comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion will be called “a solid solution hereinafter. Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered. The quicker dissolution may be attributed at least in part to the fact that the energy required for dissolution of the components from a solid solution is less than that required for the dissolution of components from a crystalline or microcrystalline solid phase. The term “a solid dispersion' also comprises dispersions which are less homogenous throughout than Solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase. For example, the term “a solid dispersion” also relates to particles having domains or small regions wherein amorphous, microcrystalline, or crystalline (a), or amorphous, microcrystalline or crystalline (b), or both, are dispersed more or less evenly in another phase comprising (b), or (a), or a solid solution comprising (a) and (b). Said domains are regions within the particles distinctively marked by some physical feature, small compared to the size of the particle as a whole, and evenly and randomly distributed throughout the particle.

Further Definitions

So as to accommodate more than 50 different compositions, sometimes similar compositions are provided under the same column under various tables. However, these are not exactly same and differ in at least one aspect from each other. To indicate the same, following terminologies have been used.

1. If any ingredient weight in mg is same for 3 batches, it is written only once.

2. If ingredient is common but weight is different, weight is written sequentially according to sequence of batches. For example, if batches are 1,2 and 3 and polymer is same but added in in three different weights such as 800 mg, 400 mg and 600 mg, it is written like batches 1/2/3 in the heading and ingredient 800 / 400 / 600 below.

3. If ingredient is not common to batches, it is written as follows,

If batches 1,2 and 3 have at least one uncommon ingredient which is present in amount 600 mg in only a. batch 1, it is written like 1/2/3 in heading and 6001 -I- below; b. batch 2, it is written like 1/2/3 in heading and -/600 /- below; c. batch 3, it is written like 1/2/3 in heading and -/-/600 below.

The present invention aims to utilize the green technology to produce amorphous form of BCS class IV drug selected from Amphotericin B, Abiraterone acetate, Furosemide, Methotrexate, Neomycin, Acetazolamide, albendazole, aprepitant, Hydrochlorothiazide, cyclosporine, Terfenadine, Bifonazole, Mesylate, Nelfinavir, Ritonavir, Indinavir, Didancosine, Taxol, Saquinavir, Ellagic acid, Ciprofloxacin, Mesalamine, aripiprazole, verapamil HC1, sulfasalazine, aloperidol, Etravirine, Digoxin, Avacopan, Avapritinib, Docetaxel, Erythromycin succinate, Ponesimod, Relugolix, Tivozanib.

The present invention aims to utilize the green technology to produce amorphous form of etravirine, more particularly, self-Emulsifying amorphous solid dispersion / solution form of Etravirine. This is achieved by employing Hot-melt Extrusion (HME) in a variety of hydrophilic polymeric carriers at a temperature below the melting point of etravirine.

More particularly, the present invention provides quick releasing compositions of BCS class IV drugs such as Etravirine which includes tablets and capsules, fast disintegrating tablets, powder for oral suspension, or any composition which can be consumed with ease without difficulty in swallowing to overcome issue of “pill burden” or dysphagia, commonly associated with large size tablets and where patient is not losing the therapeutic dose.

The quick releasing compositions of BCS class IV drugs are solvent free and contain granules prepared from extrudes which are prepared by hot melt extrusion. Mixture of Etravirine, a hydrophilic polymeric carrier and a dispersing agent / plasticizer is subjected to hot melt extrusion at the temperature below the melting point of etravirine to produces extrudes which are dried and are subjected to sifting / grinding to produce granules and granules blended with essential extra-granular material / components to produce quick release compositions of BCS class IV drugs such as Etravirine.

More particularly Etravirine undergoes degradation at its melting point. It is therefore highly unlikely for a person skilled in the art to consider hot melt extrusion for Etravirine. In the present invention, use of hot melt extrusion at a temperature below the melting point of etravirine is the driving force which prevents degradation and achieves soluble form of Etravirine in a solvent free composition and by a solvent free method. The same is applied to BCS class IV drugs where use of hot melt extrusion can be done at a temperature below the melting point of such drug.

Thus, the solubilization of the BCS class IV drug in molten polymer and / or copolymer over melting regime was opted in the conversion of crystalline to amorphous from.

More particularly, invention relates to Solvent Free Solid Oral Composition of Etravirine. Self-Emulsifying Amorphous Solid Dispersion / Solution is prepared from BCS class IV drug such as Etravirine, polymer and / or co-polymer and a suitable dispersing agent. Suitable dispersing agent in ternary mixture with Etravirine and polymer and / or co-polymer reduces / lowers down the processing temperature in hot melt extrusion as a result of reduction of the glass transition temperature of hydrophilic polymer and / or co-polymer.

Dispersing agent is melted if it is solid and used as it is if it is a liquid.

The invention also relates to process of preparing solvent free compositions of BCS class IV drugs.

The process comprises,

(a) subjecting BCS class IV drug such as Etravirine , a pharmaceutically acceptable water-soluble polymeric carrier, and a pharmaceutically acceptable dispersing agent at elevated temperature to provide an extrudable semi-solid mixture. By “elevated temperature” herein meant a temperature above which polymeric carrier starts softening, which can also be affected by other components if present, such as plasticizers or dispersing agents.

(b) extruding the semi-solid mixture, for example through a die; and

(c) cooling the resulting extrudate to provide a solid matrix comprising the polymeric carrier and the plasticizer or dispersing agent and having the API thereof dispersed resulting an essentially amorphous solid dispersion and/or solid solution therein.

A process for preparing a solvent free solid dispersion and/or solid solution for BCS class IV drug such as Etravirine is as described in details below and comprises following steps: i) Mixing BCS class IV drug such as etravirine, one or more polymer / copolymer / any combination thereof and optionally an additional agent to prepare blend; ii) Granulating blend with liquid dispersing agent / melted solid dispersing agent and kneading; iii) Drying kneaded mass and optionally milling; iv) Optionally blending dried mass with processing aids; v) Subjecting intragranular portion to hot melt extruder to prepare glassy solid solution of etravirine; vi) Extruding glassy solid solution to obtain extrudes. vii) Cooling / solidifying extrudes of etravirine and drying; viii) Milling extrudes to produce granules; ix) Blending granules with extra-granular component; x) Processing blend of step c into pharmaceutical composition of Etravirine.

BCS class IV drug is selected from Amphotericin B, Abiraterone acetate, Furosemide, Methotrexate, Neomycin, Acetazolamide, albendazole, aprepitant, Hydrochlorothiazide, cyclosporine, Terfenadine, Bifonazole, Mesylate, Nelfinavir, Ritonavir, Indinavir, Didancosine, Taxol, Saquinavir, Ellagic acid, Ciprofloxacin, Mesalamine, aripiprazole, verapamil HC1, sulfasalazine , Haloperidol, Etravirine, Digoxin, Avacopan, Avapritinib, Docetaxel, Erythromycin succinate, Ponesimod, Relugolix, Tivozanib.

Selection of polymer is crucial. Polymers and / or co-polymers having low glass transition temperature and highly miscible with the etravirine are ideal candidates to get amorphous dispersion at the temperature below the melting point of the etravirine.

Dispersing agent can also be a plasticizer or a solubilizer. Use of plasticizers is an approach to reduce the glass transition temperature of the polymer and / or copolymer. Thus, the selection of proper plasticizers/solubilizers is another key point in processing the etravirine at the temperature below the melting point.

Combining BCS class IV drug such as Etravirine, polymer and / or co-polymer and a suitable dispersing agent leads to generation of a glassy solid dispersion of etravirine enhancing solubility of etravirine which is same as or higher than marketed formulation prepared by spray drying method.

The present invention provides quick release compositions of BCS class 4 drug including Etravirine.

More particularly, the compositions are Self Emulsifying Amorphous Solid Dispersion / Solution (SEAS ² )™ of Etravirine. The in vitro release of the solid dispersions prepared in accordance with the present invention is compared with release of marketed products. Study on marketed products include study on two different Reference Listed Drug (RLD) Products containing 100 mg and 200 mg of Etravirine respectively. These RLD products were procured and tested for in vitro release profile. These two products exhibited different in vitro release profile / % Cumulative release profile when tested in 900 ml of 0.01 N HC1 at 50 RPM paddles speed. RLD product (tablet) containing 100 mg Etravirine exhibited much faster (faster RLD product) release than RLD product (tablet) containing 200 mg Etravirine (slower RLD product). The slower RLD product does not release Etravirine completely even at the end of 60 mins. Hence dissolution profile is continued till 120 minutes. But even at this time point, no substantial increase in the dissolution is found. Therefore, even spray dried product couldn’t exhibit complete release. The release of RLD products (100 mg and 200 mg) are provided in table 1.

The objective of the present invention was to achieve the desired release profiles as provided in table 1 or higher release profile. Table 1

The quick release compositions of the present invention comply with at least one, preferably two and more preferably all three release criteria given below when tested for in-vitro release / dissolution employing 900 mL Medium having 1 % SLS in 0.01N HCL, and using Dissolution Apparatus: USP Type II (Paddle) at 37.5° C

Table 2: % Release of Etravirin compositions should comply at least one of the following release pattern at 15 mins, 30 mins or 60 mins.

These compositions can be further developed into tablets, suspension, fast disintegrating tablets or powder for oral suspension, pellets composition or any other suitable composition which can be administered with ease.

Such final compositions have all the desired characteristics. They are quick releasing and hence enhance solubility and therefore bioavailability of BCS class IV drug such as Etravirine. In such compositions, substantial part of Etravirine or entire Etravirine has been converted into amorphous form (refer figure 14) without increasing bulkiness of the composition. Therefore, such compositions are much smaller in size than the spray dried composition and can be consumed with ease. They can be produced without employing large amount of organic / nonaqueous solvents and therefore the processes are easy, economical, occupy less resources and are not time consuming but faster as compared to spray drying. Figure 14 presents an X-ray diffractograms of i) pure crystalline Etravirine, ii) placebo and iii) hot melt extrudes of containing Etravirine, polymer and / or copolymer and dispersing agent. The diffractogram of extrudes clearly depicts the amorphous nature indicating that crystallinity is successfully broken down completely to enhance solubility. These compositions can be fast disintegrating tablets. They can also be formulated as powder for oral suspension. Such suspensions are storage stable and can be stored for at least 1 month once prepared, preferably 3 months once prepared. There is no fear of losing dose or inaccurately administering the dose.

Particularly, the invention provides quick release compositions comprising BCS class IV drug such as Etravirine and polymer and / or copolymers. More particularly, compositions comprise of Etravirine, polymer and / copolymers and a suitable dispersing agent / plasticizer.

Polymer and / or co-polymer can be one or more selected from vinylpyrrolidonevinyl acetate copolymers, methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, copovidone, gelatine, polyvinyl alcohol, polymethacrylates, sorbitol and other materials known to one of ordinary skill in the art.

Preferably, polymer and / or co-polymer is a hydrophilic polymer. One preferred polymer is polyvinyl pyrrolidone. PVP K-30, PVP K-12, PVP K-170 are preferred. Another preferred polymer is hydroxy propyl methyl cellulose, particularly HPMC 3 cps or Affinisol HPMC HME 100 LV.

Copolymers include pluronic copolymers, poloxamers, vinylpyrrolidone-vinyl acetate copolymers, polyethylene glycol-polyvinyl alcohol copolymers, caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and any suitable copolymer known to one of ordinary skill in the art.

Preferably, copolymer is vinylpyrrolidone-vinyl acetate copolymer. Copovidone (Kollidon® VA 64 and VIVAPHARM® PVP/VA 64) is 3:2 copolymer of 1-vinyl- 2-pyrrolidone and vinyl acetate and is one of the preferred polymers. Yet another preferred polymer is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate such as EUDRAGIT®EPO. Combination of two polymers and / or co-polymers / a polymer and a copolymer has also been employed. One embodiment has a combination of povidone and copovidone. Another preferred embodiment has employed a combination of hydroxy propyl methyl cellulose and copovidone. Yet another embodiment has employed a combination of Copovidone and polyvinyl alcohol. This combination has produced one of the best mode batches where shiny transparent / shiny translucent / slightly yellowish glassy extrudes were produced.

Etravirine compositions comprising Etravirine and polymer / copolymer often have high glass transition temperatures in absence of a dispersing agent. Physically, the extrudes may appear rough and yellowish or brownish in colour. Such extrudes are observed in batch numbers F009A, F016A, F003X etc. Dispersing agent acts as a plasticizer and helps in lowering glass transition temperatures thus producing extrudes at lower temperatures than the degradation of Etravirine.

The dispersing agent comprises a solubilizer and / or emulsifier such as preferably a non-ionic solubilizer. Preferred dispersing agent is polyethoxylated castor oil, polysorbate 80, polyethylene glycols, propylene glycol esters of caprylic (C8) and capric (CIO) acids, D-a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS), mono, di and triglycerides with PEG esters of fatty acids or their mixtures etc. D-a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) is one of the most preferred dispersing agent. Another advantage of Vitamin E TPGS is that it not only lowers down the processing temperature but is also useful as a permeability enhancer and can prove exceedingly useful for BCS class IV drugs such as Etravirine. Additionally, Amorphous dispersion can augment the apparent solubility yielding the supersaturation system and Vitamin E TPGS can help both in maintaining the supersaturation and aid in the permeability of etravirine.

Most preferred dispersing agents / plasticizers include polyethylene glycol such as PEG 6000, PEG 3350, PEG 400, Propylene Glycol, glycerol monocaprylocaprate (Labrafac MC 60), Tween 80, D-a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS), Solubilizer having Polysorbate 80 adsorbed on a porous carrier Magnesium Aluminium Silicate known as Sepitrap 80, solubilizer having Polyoxyl 40 Hydrogenated Castor Oil adsorbed on a porous carrier Magnesium Aluminium Silicate known as Sepitrap 4000, Macrogolglycerol ricinoleate / Polyoxyl 35 Castor Oil (Kolliphor EL), Sorbitol (Sorbidex), Crospovidone (Kollidon CL) and HPMC 6 cps.

The desired extrudes are shiny transparent / shiny translucent / slightly yellowish glassy extrudes. Brown coloured extrudes, elastic extrudes, rough extrudes, brittle extrudes, pasty extrudes are undesirable.

Smoke or bubble generation is sometimes noted which can be controlled by process parameters.

Batches during production of which high torque reading was noted where torque was beyond 50 or sometimes beyond 80 are not desirable batches. Batches having poor flow where feeder had to stop frequently were also not desirable ones.

Some of the problems faced and solutions sought are discussed below.

Problems faced during Hot Melt Extrusion

1. Poor flow problem

In spite of increasing solubility and enhancing dissolution profile, some hot melt extrudes suffer from poor flow characteristics. To solve this issue blend which is subjected to hot melt extrusion was added one or more processing aids. Colloidal silicon dioxide (Aerosil) is one such preferred processing aid. In most cases it improved the flow characteristics. Silicates, stearates, talc are also effective in enhancing flow properties. Calcium silicate is found particularly useful. It also aided in improving compressibility and reducing compaction force. One more processing aid is found useful which is sodium lauryl sulphate.

Thus, some of the preferred compositions contain Etravirine, polymer / copolymer, dispersing agent and a processing aid.

Selection of process parameters depend on selection of polymers /copolymers and selection of dispersing agents. If flow is good, feeder speed of from 10 RPM to 40 RPM can be employed and torque preferably below 50 is observed which is indicative of smooth functioning.

2. Browning or Degradation or of extrudes

Additionally, since Etravirine undergoes degradation at its melting temperature, experiments were conducted to arrive at compositions which are stable at high temperatures which may be encountered either during processing or due to high residence time of the material containing Etravirine. High residence time can also be encountered if there is some problem in the manufacturing. It can be related to facility related issues such as issues in air handling unit, equipment, electricity etc. It can be due to non-availability of resources. If due to any uncontrolled reason, Etravirine containing material is required to spend higher residence time in the extruder, such batch of Etravirine extrudes should remain safe and within permitted limits of assay and impurities.

Therefore, experiments were performed using a number of stabilizers which can stabilize degradation or browning of Etravirine compositions.

In these experiments, few batches are purposely subjected to high temperatures for longer duration to mimic a condition of higher residence time and checked for increase in impurities. Further, batches having same compositions were again prepared incorporating stabilizers and further subjected to such high temperature for longer time to mimic high residence time to check if stabilizer could prevent browning or degradation. These compositions containing stabilizer after subjecting to high temperatures for longer duration performed well compared to their counterpart batches without a stabilizer. Such stabilizers include antioxidants, buffering agents, amino acids, sugar alcohols with amino group modification such as meglumine etc. Meglumine is most preferred stabilizer.

Following tables provide effect on batches manufactured with and without one such stabilizer meglumine. One batch of Etravirine was intentionally subjected to higher temperatures for longer time to mimic higher residence time. A sample for HPLC analysis was taken every hour to check amounts of impurities rising with time. It can be seen that stabilizer meglumine prevented browning as well as degradation which may occur due to high residence time.

Table 3: Related substances data of batch without meglumine after analysis by HPLC

Table 4: Related substances data of batch containing meglumine after analysis by

HPLC Thus, composition of the present invention may comprise Etravirine, polymer / copolymer, dispersing agent, processing aid and a stabilizer.

Melting of extrudes is also observed in batch FO33B where PVP K-17, an ingredient having a melting point of 130°C has been employed in an amount of 66 % of the extrudes. In such cases process temperatures should be controlled to avoid melting and browning after melting.

3. Loss of compactibility after extrusion process:

Loss of compactibility is a common problem observed for high dosed hot melt extrudes. The loss of compactibility of milled extrudates compared to compactibility of “as is” physical blend prior to the extrusion is reported by many researchers. An increase in particle density and loss of voids can occur due to heat and shear stress during hot melt extrusion, which can reduce the ductility of the extruded material. The physical blend resulted in stronger tablets as compared to extruded glassy material obtained after hot melt extrusion process. This difference in the compactibility suggests that for the physical blend where no molecular level interactions are present between the particles, plastic deformation of system due to compression is greater thereby resulting in more interparticle bonding and stronger strength of tablet at a given compression force. Whereas, for the HME solid dispersions due to similar molecular level interactions between drug and polymer and / or co-polymer, the crystal lattice for the drug is completely absent and the material is glassy. As a result, these glassy materials at the same porosity may have weak interactions between the particles thereby resulting in a lower strength of the compacted tablet.

Thus, compactibility of hot melt extrudes is generally low. Another observation is that when intragranular portion of tablet is higher i.e. around from 60% to 80%, it results in a decrease in the tablet tensile strength.

Thus, screening of suitable extra-granular compositions having optimum compactibility and disintegration was a major challenge faced post extrusion.

Therefore, suitable disintegrant can be added. Disintegrants employed include crospovidone, microcrystalline cellulose, starch, sodium starch glycolate, croscaramellose sodium. Crospovidone is a highly compressible material due to its unique particle morphology; hence, lower compression force is generally required to make tablets with desired tensile strength and porosity compared to other disintegrants. Crospovidone is a porous material and acts as both binder and disintegrant in the tablet, which could result in stronger tablets compared to croscarmellose sodium and mainly Sodium Starch Glycolate (SSG). Also, Florite R, chemically calcium silicate, also helped in achieving the greater compaction. Thus, the current formulation having intragranular level of 60% to 80% along with the combination of Crospovidone and calcium silicate as an extra-granular component resulted in the Tablets with desired characteristics and also tablets for Suspension type of dosage form.

Suitable tablet compositions have from 50 - 85 % w/w extrudes and from 15 - 50 % w/w extra-granular material / component. Preferably, tablet compositions have from 55 - 75 % w/w extrudes and from 25 - 45 % w/w extra- granular material / component. Preferably, powder for oral suspension has from 55 - 85 % w/w extrudes and from 15 - 45 % w/w extra- granular material / component. Extra- granular material / component comprises one or more of disintegrant, diluent, glidant , lubricant, processing aid. Preferably, extra-granular material / component has from 30-70 % w/w of disintegrant, 10 - 30 % w/w diluent, up to 8 % w/w of total of glidant and lubricant and from 10 - 40 % of processing aid such as calcium silicate in terms of % w/w of extra-granular material / component. In terms of final composition such as tablet, % extra-granular material / componnet comprise from 10 - 25 % of disintegrant, preferably from 12 to 22 % of disintegrant, up to 15 % and preferably up to 10 % of diluent, up to 3 %, preferably up to 2.5 % or up to 2 % of total of glidant and lubricant and up to 15 % or from 1 - 12 % of processing aid.

Example 8 provides tablet composition prepared from milled extrudes containing Etravirine, Copovidone as polymer, Vitamin E TPGS as dispersing agent and colloidal silicon dioxide (Aerosil) as intragranular processing aid,

The composition of the invention are prepared by a Solvent free process which does not employ non-aqueous / organic solvents. Suitable process includes hot melt granulation or hot melt extrusion.

Etravirine is reported to get decomposed at its melting temperature making it not an ideal candidate for hot melt extrusion processes. However, when dispersing agent is added to etravirine -polymer blend, combination of Etravirine, polymer and / copolymers and a suitable dispersing agent reduces / lowers down the processing temperature in hot melt extrusion as a result of reduction of the glass transition temperature of hydrophilic polymer. This leads to generation of a glassy solid dispersion of etravirine enhancing solubility of etravirine. Role of dispersing agent is two-folds. It generates glassy solid dispersion and also owing to its HLB value helps in formulating self-micro emulsifying glassy solid dispersion / solution system.

Such system not only helps in enhancing in the solubility and dissolution rate of etravirine but also help in the permeability rate of etravirine, a typical BCS IV molecule.

Preparing glassy solid dispersion of etravirine at a processing temperature below the melting point of etravirine is a major challenge in hot melt extrusion technology. This lowering of temperature is essential because otherwise etravirine degrades or decomposes at its melting temperature.

Etravirine melting point is around 260-265°C, more particularly, 262-265°C. This temperature causes degradation of Etravirine. Thus, the high melting and thermolabile drugs like etravirine poses substantial challenge during the development of amorphous solid dispersion using melt extrusion technology.

The hurdle in preparing glassy solid dispersion of etravirine is owing to its high melting point and degradation upon melting. Inclusion of dispersing agent as a tertiary component in the drug-polymer and / or copolymer binary blend has found to be useful in lowering down the processing temperature in HME as a result of reduction of the glass transition temperature of hydrophilic polymer / copolymer.

Thus, it has been found that such hot melt granulations can be conducted at a temperature not exceeding 225°C, preferably not exceeding 215°C, more preferably not exceeding 210°C and most preferably not exceeding 200°C.

This gap in temperature of around 40 - 60°C between production of glassy solid dispersion of etravirine leading to Self-Emulsifying Amorphous Solid Dispersion / Solution of Etravirine and degradation temperature of Etravirine enables achieving all desired characteristics of product sand process such as Enhanced solubility and bioavailability, Reduced Bulkiness, accurate dosing, ease of administration / consumption of Etravirine compositions, Solvent free, easy, economical process complying with Green Chemistry initiative. The same criterion is applicable for other BCS class IV drugs where melting temperature lower than melting points of BCS class IV drug can be applied. The difference in the temperatures can be around 25 °C or more and preferably around 40°C - 60°C.

Process of manufacturing extrudes is a multi-step process. First step, granulate is prepared in a suitable mixer such as rapid mixer granulator. Etravirine and polymer / copolymer is blended and granulated by employing liquid / molten dispersing agent. Dispersing agent is melted to liquid form for granulation. Some of the dispersing agents are already in liquid form. Granulation and kneading are done in rapid mixer granulator. The kneaded mass is dried, optionally milled and blended with suitable intragranular processing aid such as colloidal silicon dioxide or calcium silicate etc.

Intragranular material / portion is then subjected to Hot melt extruder (HME). Alternatively, mixing, granulation and kneading can be entirely done in a Hot melt extruder.

Hot melt extrusion is carried out in hot melt extruder. The extruder has multiple conveying zones which can be maintained at varying temperatures zones. At least 2-3 zones of varying temperatures can be employed in the extruder. These zones are at elevated temperatures from 40 - 225 °C. As an alternative to rapid mixer granulator, HME can be used for granulation and kneading.

Once material is added to HME, various operations can be performed such as blending, kneading, melting, etc. by subjecting materials to various zones maintained at various elevated temperatures.

Depending on the contents of a blend, at least three or more than three elevated temperatures zones are employed in the extruder. Melting zone should have a temperature responsible to cause melting of blend. Elevated temperature varies from 40°C to 225°C. In an embodiment 5 elevated temperature zones such as 40°C, 70°, 170°C, 200°C and 220°C have been employed. In yet another embodiment, 4 elevated temperature zones such as 40°C, 70°, 170°C, and 200°C have been employed. In yet another embodiment, 5 elevated temperature zones such as 50°C, 90°, 130°C, 150°C and 160°C have been employed. In one more embodiment, 6 elevated temperature zones such as 100°C, 140°, 175°C, 180°C, 190°C and 200°C have been employed.

After drying of extrudes, they are milled and passed through ASTM #40 mesh to obtain granules. . The granules obtained are then blended properly with the extra- granular ingredients.

Extra-granular material / component comprises one or more of disintegrant, diluent, glidant , lubricant, processing aid. Preferably, extra-granular material / component has from 30-70 % w/w of disintegrant, 10 - 30 % w/w diluent, up to 8 % w/w of total of glidant and lubricant and from 10 - 40 % of processing aid such as calcium silicate in terms of % w/w of extra- granular material / components.

The Self-Emulsifying Amorphous Solid Dispersion / Solution of Etravirine is further blended with one or more diluents, one or more disintegrants, one or more binders, glidants, lubricants and extra-granular processing aids etc. and compressed to produce a tablet, preferably a fast disintegrating tablet or tablets for Suspension type of dosage form.

Such compressed tablets are less bulky and occupy less than 75 %, preferably less than 60 % and more preferably up to or less than 50 % weight of the marketed tablets.

Preferably, The Self-Emulsifying Amorphous Solid Dispersion / Solution of Etravirine is further blended with one or more suspending agents, one or more diluents, one or more sweeteners, flavouring agents etc. and blended to produce powder for oral suspension / suspension. Present invention provides novel self-emulsifying amorphous solid dispersion resulting in pharmaceutical compositions with enhanced solubility and thereby enhanced bioavailability for BCS class IV drugs.

Etravirine Quick Release compositions of the present invention release Etravirine at the same rate as that of RLD product or preferably at least 10 %, more preferably at least 15 % and most preferably at least 25 % faster than RLD product.

The release patterns should be in accordance with limits set in table 2.

With compositions releasing faster than RLD product, it is expected that when administered in-vivo it should result into up to 25%, specifically up to 15 % and more specifically up to 10% higher bioavailability compared to Reference Listed product and provides solution to problems generally encountered with BCS class IV drugs. With compositions having similar release pattern to that of RLD product, it is expected that when administered in-vivo it should result into similar bioavailability as that of RLD product. Hot melt extrudes of Etravirine of the present invention comprising Etravirine, polymer and / or copolymer and dispersing agent solve issues of solubility and permeability, however, Etravirine has one more problem. It degrades at its melting point and hence not a suitable candidate for hot melt extrusion. Therefore, merely using Etravirine and polymer mixture for hot melt extrusion has not worked when tried by the inventors. Careful selection of polymer and / or copolymer or their combination along with suitable dispersing agent which can help in reducing glass transition temperature of selected polymer and / or copolymer producing desired extrudes is important. The desired extrudes are shiny transparent / shiny translucent / slightly yellowish glassy extrudes.

Brown coloured extrudes, elastic extrudes, rough extrudes, brittle extrudes, pasty extrudes are undesirable. Smoke or bubble generation is sometimes noted which can be controlled by process parameters.

Batches during production of which high torque reading was noted where torque was beyond 50 or sometimes beyond 80 are not desirable batches. Batches having poor flow where feeder had to stop frequently were also not desirable ones. The specification enumerates various challenges encountered in arriving at the desired extrudes of Etravirine which indicates that mere mention of suggestion of employing hot melt extrusion for Etravirine or similar pharmaceutical substances does not enable a person skilled in the art to arrive at desired final product which is a quick release composition of Etravirine.

The final quick release composition can be tablet or capsule or fast disintegrating tablet or powder for suspension or powder / granules for sachet etc.

When the composition is a Powder for suspension form, it should be dispersed in purified water before administration for providing ease to patients. When dispersed in purified water, the composition is present in ready to drink suspension form and can be administered using volumetric doser.

Because Reference marketed product is a tablet, most compositions are compressed into tablets for checking in vitro release profile and comparing the same with Reference / marketed product. It is surprisingly noted that two different strengths of reference / marketed product viz. 100 mg and 200 mg have different release pattern. This also can relate to low solubility of high dose. Hence most of the batches provided contain higher dose viz. 200 mg than lower dose 100 mg.

The tablets are compressed at hardness of about 6 kP to about 15 kP, specifically 9 kp to 12 kp, wherein said tablets achieve complete disintegration in less than about 5 minutes, specifically in less than 3 minutes and more specifically in less than 60 seconds, in a tablet disintegration test using purified water at 37° C.

The quick release compositions of Etravirine preferably employ hydrophilic polymers / copolymers / combinations thereof. Copovidone (Kollidon® VA 64 and VIVAPHARM® PVP/VA 64) which is 3:2 copolymer of l-vinyl-2-pyrrolidone and vinyl acetate is one of the preferred polymers. Combination of polymers and / or co-polymers / a polymer and a copolymer has also been employed. One preferred embodiment has a combination of povidone and copovidone. Another preferred embodiment has employed a combination of hydroxy propyl methyl cellulose and copovidone. Yet another embodiment has employed a combination of Copovidone and polyvinyl alcohol. This combination has produced one of the best mode batches where white translucent, shiny extrudes were produced.

Several dispersing agents are found useful. Most preferred is D-a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS). Compositions comprising Copovidone and D-a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) and a BCS Class IV compound is found particularly useful.

The quick release compositions of BCS Class IV drugs such as Etravirine are less bulky and occupy less than 75 %, preferably less than 60 % and more preferably up to or less than 50 % weight of the marketed tablets.

The quick release compositions such as powder for oral suspension or tablet compositions have from 50 - 85 % w/w extrudes and from 15 - 50 % w/w extra- granular material / component. Preferably, tablet compositions have from 55 - 75 % w/w extrudes and from 25 - 45 % w/w extra-granular material / component. Preferably, powder for oral suspension have from 55 - 85 % w/w extrudes and from 15 - 45 % w/w extra-granular material / component. Extra-granular material / component comprises one or more of disintegrant, diluent, glidant , lubricant, processing aid.

Preferably, extra-granular material / component has from 30 -70 % w/w of disintegrant, 10 - 30 % w/w diluent, up to 8 % w/w of total of glidant and lubricant and from 10 - 40 % of processing aid such as calcium silicate in terms of % w/w of extra-granular material / components. In terms of final composition such as tablet, % extra-granular material / components comprise from 10 - 25 % of disintegrant, preferably from 12 to 22 % of disintegrant, up to 15 % and preferably up to 10 % of diluent, up to 3 %, preferably up to 2.5 % or up to 2 % of total of glidant and lubricant and up to 15 % or from 1 - 12 % of processing aid.

Processing aids facilitate preparation of compositions. Suitable processing aid includes colloidal silicon dioxide (Aerosil) as one preferred processing aid. In most cases it improved the flow characteristics. Silicates, stearates, talc are also effective in enhancing flow properties. Calcium silicate is found particularly useful. It also aided in improving compressibility and reducing compaction force. One more processing aid is found useful which is sodium lauryl sulphate.

Additionally, since Etravirine undergoes degradation at its melting temperature, experiments were conducted to arrive at compositions which are stable at high temperatures which may be encountered either during processing or due to high residence time of the material containing Etravirine. High residence time can also be encountered if there is some problem in the manufacturing. It can be related to facility related issues such as issues in air handling unit, equipment, electricity etc. It can be due to non-availability of resources. If due to any uncontrolled reason, Etravirine containing material is required to spend higher residence time in the extruder, such batch of Etravirine extrudes should remain safe and within permitted limits of assay and impurities. Therefore, additionally, a stabilizer is preferably added. Stabilizer is selected from antioxidants, buffering agents, amino acids, sugar alcohols with amino group modification such as meglumine etc. Meglumine is most preferred stabilizer.

Therefore, quick release compositions of the present invention comprise of BCS class IV drug such as Etravirine, hydrophilic polymer, dispersing agent and optionally, a processing aid and optionally a stabilizer.

Additionally, to impart taste to powder for oral suspensions, flavours, sweeteners. Taste modifiers etc. are employed.

Process of manufacturing extrudes is a multi- step process. First step, granulate is prepared in a suitable mixer such as rapid mixer granulator. Etravirine and polymer / copolymer is blended and granulated by employing liquid / molten dispersing agent. Dispersing agent is melted to liquid form for granulation. Some of the dispersing agents are already in liquid form and are sprayed directly. Granulation and kneading are done in rapid mixer granulator. The kneaded mass is dried, optionally milled and blended with suitable intragranular processing aid such as colloidal silicon disoxide or calcium silicate etc. to produce intragranular material. Intragranular material / portion is then subjected to Hot melt extruder (HME) where it is subjected to one or more zones, preferably, multiple conveying zones of elevated temperatures, preferably at least 2-3 zones of varying temperatures to produce glassy solid solution of Etravirine. These zones of varying temperatures are at elevated temperatures from 40 - 225 °C. Glassy solid solution is extruded as extrudes which are shiny transparent / shiny translucent / slightly yellowish glassy extrudes.

Alternatively, mixing, granulation by melting, kneading can be entirely done in a Hot melt extruder.

Hot melt extrusion is carried out in hot melt extruder. The extruder has multiple conveying zones which can be maintained at varying temperatures zones. At least 2-3 zones of varying temperatures can be employed in the extruder. These zones are at elevated temperatures from 40 - 225 °C.

As an alternative to rapid mixer granulator, HME can be used for granulation and kneading.

Once material is added to HME, various operations can be performed such as blending, kneading, melting, formation of glassy solution, extrusion of extrudes. Depending on the contents of a blend, at least 2 - 3, preferably, three or more than three elevated temperatures zones are employed in the extruder. Melting zone should have a temperature responsible to cause melting of blend.

Elevated temperature varies from 40°C to 225 °C. In an embodiment 5 elevated temperature zones such as 40°C, 70°, 170°C, 200°C and 220°C have been employed. In yet another embodiment, 4 elevated temperature zones such as 40°C, 70°, 170°C, and 200°C have been employed. In yet another embodiment, 5 elevated temperature zones such as 50°C, 90°, 130°C, 150°C and 160°C have been employed. In one more embodiment, 6 elevated temperature zones such as 100°C, 140°, 175°C, 180°C, 190°C and 200°C have been employed. Once outside the hot melt extruder, extrudes are cooled / solidified, and milled to produce granules. Granules are blended with extra- granular material / components and final desired products are produced.

Thus, the present invention aims to utilize “Green Technology” in preparation of amorphous form of BCS class IV drug such as etravirine, more particularly, self- Emulsifying amorphous solid dispersion / solution form of Etravirine. This is achieved by employing Hot-melt Extrusion (HME) of BCS class IV drug in a variety of hydrophilic polymeric carriers and dispersing agents at a temperature below the melting point of such drug such as etravirine. The composition and process thus provides amorphous form of drug in a composition for better patient compliance having ease of administration.

BCS class IV drug is selected from Amphotericin B, Abiraterone acetate, Furosemide, Methotrexate, Neomycin, Acetazolamide, albendazole, aprepitant, Hydrochlorothiazide, cyclosporine, Terfenadine, Bifonazole, Mesylate, Nelfinavir, Ritonavir, Indinavir, Didancosine, Taxol, Saquinavir, Ellagic acid, Ciprofloxacin, Mesalamine, aripiprazole, verapamil HC1, sulfasalazine , Haloperidol, Etravirine, Digoxin, Avacopan, Avapritinib, Docetaxel, Erythromycin succinate, Ponesimod, Relugolix, Tivozanib.

Following examples describe invention without limiting the scope of the invention.

Example 1

Table 5: self-micro emulsifying glassy solid dispersion / solution Process

1. Etravirine and Kollidone VA 64 are passed-through ASTM 40 Mesh and are mixed to produce blend.

2. Kolliphor EL / Vitamin E TPGS / PEG 3300 is mixed with step 1 blend.

3. The step 2 blend is passed using HME at Temp. NMT 200 °C. to produce glassy solid solution. The glassy solid solution is cooled and the extrudes are passed through mill.

Example 2 Table 6: Powder for oral suspension

Process 1. Etravirine and Kollidone VA 64 are passed-through ASTM 40 Mesh and are mixed to produce blend.

2. Kolliphor EL / Vitamin E TPGS / PEG 3300 is mixed with step 1 blend.

3. The step 2 blend is passed using HME at Temp. NMT 200 Deg C. to produce glassy solid solution. 4. The glassy solid solution is cooled and the extrudes are passed through mill.

5. Mix the powdered / milled solid solution with suspension agent / suspending agent preferably, HPMC E 15, preservative preferably, Sodium Benzoate, , sweetener preferably, sucralose, flavoring agent such as mint etc. and passed through 40 mesh before blending for 15 min. 6. Mix 10 ml of water in equivalent to 200 mg Etravirine blend is mixed and shaken well.

7. Dose mentioned in table 4 is withdrawn using suitable syringe. Table 4 provides dose delivered from such suspension.

Example 3

Table 7

Example 4: In vitro release / dissolution profile employing following conditions: Dissolution medium: Volume: 900 mL Medium: 1% SLS in 0.01N HCL, Apparatus: USP Type II (Paddle) at 37.5° C.

The in vitro release profile is as shown in table 8. Table 8 Example 5, table 9

Example 6, Table 10

Example 7, Table 11

Optimization trials

Following optimization trials are taken i) To check effects of polymeric carriers (batches F064A, F095A). ii) To minimize degradation when exposed at high temperature (batches F077O and F079C). iii) To study the effect of polymer and plasticizer concentration on the HME processability (batches F074A and F082M). iv) To study the effect of meglumine on the HME processability and dissolution rate of etravirine (batches F084A and FO88D). v) To study the effect of compensating Kollidon VA 64 with HPMC in the HME composition (batches F094C and FO88E) vi) To study the effect of TPGS and PEG 3350 as different plasticizers on the extrusion process and the dissolution rate of etravirine. (batches F090A and F091A) vii) To study the effect of copovidone from different vendors (BASF vs JRS) on the extrudability and dissolution rate of etravirine. viii) To incorporate the precipitation inhibitors along with the polymer and study the impact on the HME process and dissolution rate of etravirine (batches F100C and F107C). ix) Optimized / Miscellaneous Batches (batches F057A, F075I, F093A). x) Batches for preparing Etravirin suspension (batches F031E and F032E).

Examples for Etravirine Tablets 200 mg

Objective: To prepare Hot-melt Extrusion (HME)-based amorphous solid dispersion of etravirine using various polymeric carriers

Table 12A: Composition of test batches with different hydrophilic polymers Manufacturing process:

1. All the ingredients were weighed accurately and separately.

2. API and Kollidon VA64/HPMC were premixed.

3. Blend in step 2 was then fed into High shear Rapid mixer granulator (RMG), and dry mixed for 15 minutes.

4. Vitamin E TPGS was melted on hot plate and then added to the dry mixed blend of step 3 in RMG and granulated for 2 minutes.

5. Granulated mixture of step 4 was kneaded for 1 minute.

6. Aerosil 200 was passed through ASTM #40 and added to the step 5 and further kneading was given for 2 minutes.

7. The granules of step 6 was then passed through ASTM # 20

8. The final blend in step 7 was fed into HME while maintaining a product temperature from range of about 40°C to 200°C.

9. Translucent/Opaque extrudes obtained in step 8 were then milled and passed through ASTM #40 mesh.

10. Granules obtained in step 9 were blended with the extra-granular ingredients mentioned in the table above.

Table 12B: Comparative release profile of F064A with the RLD 200 mg. (Refer Figure 1)

Objective: To design the HME batches with the aim to enhance the solubility and simultaneously minimize the degradation of etravirine when exposed at high temperature.

Table 13 A: Trial HME batches with various compositions

Manufacturing process:

1. All the ingredients were weighed accurately and separately. 2. API and Kollidon VA64 (also meglumine in case of F079C) were premixed.

3. Blend in step 2 was then fed into High shear Rapid mixer granulator (RMG), and dry mixed for 15 minutes. 4. Vitamin E TPGS was melted on hot plate and then added to the dry mixed blend of step 3 in RMG and granulated for 2 minutes.

5. Granulated mixture of step 4 was kneaded for 1 minute.

6. Aerosil 200/Florite R/SLS was passed through ASTM #40 and added to the step 5 and further kneading was given for 2 minutes.

7. The granules of step 6 was then passed through ASTM # 20

8. The final blend in step 7 was fed into HME while maintaining a product temperature from range of about 40°C to 200°C.

9. Extrudes obtained in step 8 were then milled and passed through ASTM #40 mesh.

10. The granules obtained in step 9 blended properly with the extra-granular ingredients mentioned above.

Table 13B: Comparative release profiles of test batches in single phase dissolution condition (Refer figure 2). Objective: To study the effect of polymer and plasticizer concentration on the HME processability.

Table 14A: Batches designed to study the effect of polymer concentration on the HME processability.

Manufacturing process:

1. All the ingredients were weighed accurately and separately.

2. API and Kollidon VA64 were premixed. 3. Blend in step 2 was then fed into High shear Rapid mixer granulator (RMG), and dry mixed for 15 minutes.

4. Vitamin E TPGS was melted on hot plate and then added to the dry mixed blend of step 3 in RMG and granulated for 2 minutes.

5. Granulated mixture of step 4 was kneaded for 1 minute. 6. Aerosil 200 was passed through ASTM #40 and added to the step 5 and further kneading was given for 2 minutes.

7. The granules of step 6 were then passed through ASTM # 20 8. The final blend in step 7 was fed into HME while maintaining a product temperature from range of about 40°C to 200°C.

9. Extrudes obtained in step 8 were then milled and passed through ASTM #40 mesh. Conclusion: Though lower TPGS did not pose any difficulty in getting transparent extrudes, incomplete granulation resulted poor blend flow. Thus, 160 mg TPGS is said to be the optimum concentration for both the granulation and extrudability.

Objective: To study the effect of meglumine on the HME processability and dissolution rate of etravirine

Table 15 A: Trial HME batches with and without meglumine

Manufacturing process:

1. All the ingredients were weighed accurately and separately. 2. API and Kollidon VA64 were premixed.

3. Vitamin E TPGS was melted on hot plate and then added to the dry mixed blend of step 2 and granulated properly.

4. Aerosil 200/Meglumine was passed through ASTM #40 and added to the step 3 and blended properly. 5. The granules of step 4 were then passed through ASTM # 20

6. The final blend in step 5 was fed into HME while maintaining a product temperature from range of about 40°C to 220°C.

7. Extrudes obtained in step 6 were then milled and passed through ASTM #40 mesh. 8. The granules obtained in step 9 blended properly with the extra granular ingredients mentioned above.

Table 15B: Comparative release profiles of test batches in single phase dissolution condition (Refer figure 3).

Objective: To study the effect of compensating Kollidon VA 64 with HPMC in the HME composition Table 16A: Batches designed compensating Kollidon VA 64 with HPMC

❖ Manufacturing process:

1. All the ingredients were weighed accurately and separately. 2. API, Kollidon VA64 and/or HPMC were premixed.

3. Vitamin E TPGS was melted on hot plate and then added to the dry mixed blend of step 2 and granulated properly.

4. Aerosil 200/Meglumine was passed through ASTM #40 and added to the step 3 and blended properly. 5. The granules of step 4 were then passed through ASTM # 20

6. The final blend in step 5 was fed into HME while maintaining a product temperature from range of about 40°C to 200°C.

7. Extrudes obtained in step 6 were then milled and passed through ASTM #40 mesh. 8. The granules obtained in step 7 blended properly with the extra granular ingredients as mentioned above.

Table 16B: Comparative release profiles of test batches in single phase dissolution condition. (Refer figure 4). the extrusion process and the dissolution rate of etravirine.

Table 17A: Batches designed to study the impact of PEG 3350 as an optional plasticizer.

Manufacturing process:

1. All the ingredients were weighed accurately and separately.

2. API, Kollidon VA64, HPMC and/or PEG 3350 were premixed.

3. In batch F090A Vitamin E TPGS was melted on hot plate and then added to the dry mixed blend of step 2 and granulated properly. Whereas in batch F091A the dry mixed blend of step 2 along with PEG3350 was heated on hot plate constant mixing and then cooled which led to the formation of free-flowing granules.

4. Aerosil 200 was passed through ASTM #40 and added to the step 3 and blended properly.

5. The granules of step 4 were then passed through ASTM # 20

6. Meglumine was passed through ASTM #40 and added to step 5 and blended properly.

7. The final blend in step 6 was fed into HME while maintaining a product temperature from range of about 40°C to 220°C.

8. Extrudes obtained in step 7 were then milled and passed through ASTM #40 mesh.

9. The granules obtained in step 8 blended properly with the extra granular ingredients as mentioned above.

Table 17B: Comparative release profiles of test batches in single phase dissolution condition. (Refer figure 5).

Objective: To study the effect of copovidone from different vendors (BASF vs JRS) on the extrudability and dissolution rate of etravirine.

Table 18A: Batches designed to study the impact of copovidone vendor.

Manufacturing process:

1. All the ingredients were weighed accurately and separately.

2. API and Kollidon VA64 were premixed.

3. Vitamin E TPGS was melted on hot plate and then added to the dry mixed blend of step 2 and granulated properly.

4. Aerosil 200 was passed through ASTM #40 and added to the step 3 and blended properly.

5. The granules of step 4 were then passed through ASTM # 20

6. The final blend in step 5 was fed into HME while maintaining a product temperature from range of about 40°C to 200°C.

7. Extrudes obtained in step 6 were then milled and passed through ASTM #40 mesh.

8. The granules obtained in step 7 blended properly with the extra granular ingredients as mentioned above.

Table 18B: Comparative release profiles of test batches in single phase dissolution condition. (Refer Figure 6).

Objective: To incorporate the precipitation inhibitors along with the polymer and study the impact on the HME process and dissolution rate of etravirine.

Table 19A: Batches designed to study the impact of precipitation inhibitor.

Manufacturing process:

1. All the ingredients were weighed accurately and separately.

2. API, Kollidon VA64, and MCC/PVA were premixed.

3. Vitamin E TPGS was melted on hot plate and then added to the dry mixed blend of step 2 and granulated properly.

4. Aerosil 200 was passed through ASTM #40 and added to the step 3 and blended properly.

5. The granules of step 4 were then passed through ASTM # 20

6. The final blend in step 5 was fed into HME while maintaining a product temperature from range of about 40°C to 200°C.

7. Extrudes obtained in step 6 were then milled and passed through ASTM #40 mesh.

8. The granules obtained in step 7 blended properly with the extra granular ingredients as mentioned above.

Table 19B: Comparative release profiles of test batches in single phase dissolution condition. (Refer figure 7).

Miscellaneous Batches:

Table 20: Miscellaneous HME Batches

Etravirine Suspension compositions

Objective 1: To prepare Hot- melt Extrusion (HME)-based amorphous solid dispersion of etravirine using different plasticizers.

Table 21A: Composition of test batches with different emulsifiers

Manufacturing process:

1. All the ingredients were weighed accurately and separately.

2. API and Kollidon VA64 were premixed in the ratio 1:4. 3. Kolliphor EL (F03 IE) was weighed and added to the blend in step 2.

4. In the case of batch F032E, melted TPGS was slowly added to the blend of step 2 and mixed and granulated manually.

5. The blend in step 3 and step 4 was fed into HME while maintaining a product temperature from about 140°C to 190°C. 6. Extrudes obtained in step 4 were then milled and passed through ASTM #40 mesh.

7. Granules, HPMC E15, Sodium benzoate, Sucralose, and Flavor were transferred to beaker and water was added into it and stirred for 30 minutes. Table 21B: Comparative release profiles of F032E with the RLD 200 mg

Objective 2: To study the effect of TPGS and PEG 3350 as different plasticizers/emulsifiers on the extrusion process and the dissolution rate of etravirine. Table 22A: Trial HME batches with TPGS and PEG 3350 compositions

❖ Manufacturing process:

1. All the ingredients were weighed accurately and separately. 2. API, Kollidon VA64, HPMC and/or PEG 3350 were premixed.

3. In batch F034F, Vitamin E TPGS was melted on hot plate and then added to the dry mixed blend of step 2 and granulated properly. Whereas in batch F035F the dry mixed blend of step 2 along with PEG3350 was heated on hot plate constant mixing and then cooled which led to the formation of free-flowing granules. 4. The final blend in step 3 was fed into HME while maintaining a product temperature from about 150°C to 190°C.

5. Extrudes obtained in step 5 were then milled and passed through ASTM #40 mesh. 6. Granules, HPMC E15, Sodium benzoate, Sucralose, and Flavor were transferred to beaker and water was added into it and stirred for 30 minutes.

Table 22B: Comparative release profiles of test batches in single phase dissolution condition. (Refer figure 9).

Objective 3: To design the batches with and without suspending agent.

Table 23A: Batches with and without suspending agent.

Manufacturing process:

1. All the ingredients were weighed accurately and separately. 2. API and Kollidon VA64 were premixed and fed into High shear Rapid mixer granulator (RMG), and dry mixed for 10 minutes.

3. Vitamin E TPGS was melted on hot plate and then added to the dry mixed blend of step 3 in RMG and granulated for 2 minutes.

4. Granulated mixture of step 3 was kneaded for 1 minute. 5. Aerosil 200 was passed through ASTM #40 and added to the step 4 and further kneading was given for 2 minutes.

6. The granules of step 6 was then passed through ASTM # 20

7. The final blend in step 6 was fed into HME while maintaining a product temperature from about 70°C to 200°C. 8. Extrudes obtained in step 7 were then milled and passed through ASTM #40 mesh.

9. Granules, Sodium Benzoate, Sucralose, Flavor and/or HPMC E15 were mixed to prepare powder for suspension. 10. Weighed quantity of powder for suspension was added in to water.

11. Step 10 was homogenized at 1500 rpm for 15 minutes where thick cake is formed.

The suspension was homogenized at increased rpm up to 5000 rpm till the thin suspension was formed.

Table 23B: Comparative release profiles of test batches in single phase dissolution condition Objective 4: To incorporate Kollidon 12 PF and study the impact on the HME process and dissolution rate of etravirine. Meglumine was added in the composition to prevent the degradation of etravirine during HME process.

Table 24A: Batches designed to study the impact of PVP K 12

Manufacturing process:

1. All the ingredients were weighed accurately and separately. 2. API and all other components as mentioned in table 6 were premixed and fed into High shear Rapid mixer granulator (RMG) , and dry mixed for 10 minutes.

3. Vitamin E TPGS was melted on hot plate and then added to the dry mixed blend of step 3 in RMG and granulated for 2 minutes.

4. Granulated mixture of step 3 was kneaded for 1 minute. 5. Aerosil 200 was passed through ASTM #40 and added to the step 4 and further kneading was given for 2 minutes.

6. The granules of step 6 was then passed through ASTM # 20

7. The final blend in step 6 was fed into HME while maintaining a product temperature from about 70°C to 200°C. 8. Extrudes obtained in step 7 were then milled and passed through ASTM #40 mesh.

9. Granules, Sodium Benzoate, Sucralose, Flavor and/or HPMC E15 were mixed to prepare powder for suspension.

10. Weighed quantity of powder for suspension was added in to water. 11. Step 10 was homogenized at 1500 rpm for 15 minutes where thick cake is formed.

12. The suspension was homogenized at increased rpm up to 5000 rpm till the thin suspension was formed. Table 24B: Comparative release profiles of test batches in single phase dissolution condition. (Refer figure 11).

Objective 5. To take a HME trial using different vendor of co-povidone as a polymeric carrier for amorphous solid dispersion (ASD)

Table 25 A: Compositions having two different vendors of co-povidone.

Manufacturing process:

1. All the ingredients were weighed accurately and separately. 2. API and co-povidone were premixed and fed into High shear Rapid mixer granulator(RMG) , and dry mixed for 10 minutes.

3. Vitamin E TPGS was melted on hot plate and then added to the dry mixed blend of step 3 in RMG and granulated for 2 minutes.

4. Granulated mixture of step 3 was kneaded for 1 minute. 5. Aerosil 200 was passed through ASTM #40 and added to the step 4 and further kneading was given for 2 minutes.

6. The granules of step 6 was then passed through ASTM # 20

7. The final blend in step 6 was fed into HME while maintaining a product temperature from about 70°C to 200°C. 8. Extrudes obtained in step 7 were then milled and passed through ASTM #40 mesh.

9. Granules were added slowly into beaker containing required quantity of water under continuous stirring.

10. Step 9 was continuously stirred until colloidal suspension was formed. 11. Weighed quantity of sodium benzoate, sucralose and peppermint flavor was added one by one into step 10 with continuous stirring.

12. Step 11 was kept under stirring for 15 minutes. Table 25B: Comparative release profiles of test batches in single phase dissolution condition. (Refer figure 12).

Objective 6: To formulate a powder for suspension batch as a new dosage form.

This formulation needs to be reconstituted before use.

Table 26A: Powder for suspension composition

Manufacturing process:

1. All the ingredients were weighed accurately and separately. 2. API and PVP/VA64 were premixed and fed into High shear Rapid mixer granulator(RMG) , and dry mixed for 10 minutes.

3. Vitamin E TPGS was melted on hot plate and then added to the dry mixed blend of step 3 in RMG and granulated for 2 minutes.

4. Granulated mixture of step 3 was kneaded for 1 minute. 5. Aerosil 200 was passed through ASTM #40 and added to the step 4 and further kneading was given for 2 minutes.

6. The granules of step 6 was then passed through ASTM # 20

7. The final blend in step 6 was fed into HME while maintaining a product temperature from about 70°C to 200°C. 8. Extrudes obtained in step 7 were then milled and passed through ASTM #40 mesh.

9. Granules, Sodium benzoate , Sucralose and Flavor were co-sifted through ASTM #40 and blended manually. 10. Sodium bicarbonate, Florite R, Ceolus UF 702, Kollidon CL were co-sifted through ASTM #40 and added to step 9 and blend was properly blended.

11. Magnesium Stearate was then added to step 10 after passing through ASTM# 60 and blended manually.

Table 26B: Comparative release profiles of test batches in single phase dissolution condition. (Refer figure 13). Reference

Mikal Rekdal, Aravind pai, Muddukrishna BS, Experimental data of co-crystals of Etravirine and L-tartaric acid, Data in Brief, Volume 16, 2018, Pages 135-140, ISSN 2352-3409, https://doi.org/10.1016Zi.dib.2017.ll.019.