Preparation Of Amorphous Solid Dispersions Research Articles

The comparison of melt technologies based on mesoporous carriers for improved carvedilol dissolution

High-shear (HS) melt granulation and hot melt extrusion (HME) were compared as perspective melt-based technologies for preparation of amorphous solid dispersions (ASDs). ASDs were prepared using mesoporous carriers (SyloidⓇ 244FP or NeusilinⓇ US2), which were loaded with carvedilol dispersed in polymeric matrix (polyethylene glycol 6000 or SoluplusⓇ). Formulations with high carvedilol content were obtained either by HME (11 extrudates with polymer:carrier ratio 1:1) or HS granulation (6 granulates with polymer:carrier ratio 3:1).DSC and XRD analysis confirmed the absence of crystalline carvedilol for the majority of prepared ADSs, thus confirming the stabilizing effect of selected polymers and carriers over amorphous carvedilol. HME produced larger particles compared to HS melt granulation, which was in line with better flow time and Carr index of extrudates. Moreover, SEM images revealed smoother surface of ASDs obtained by HME, contributing to less obstructed flow. The rougher and more porous surface of HS granules was correlated to larger granule specific surface area, manifesting in faster carvedilol release from SyloidⓇ 244FP-based granules, as compared to their HME counterparts. Regarding dissolution, the two HS-formulations performed superior to pure crystalline carvedilol, thereby confirming the suitability of HS melt granulation for developing dosage forms with improved carvedilol dissolution.

Preparation, Characterization and Evaluation of Nintedanib Amorphous Solid Dispersions with Enhanced Oral Bioavailability.

The dissolution and bioavailability challenges posed by poorly water-soluble drugs continue to drive innovation in pharmaceutical formulation design. Nintedanib (NDNB) is a typical BCS class II drug that has been utilized to treat idiopathic pulmonary fibrosis (IPF). Due to the low solubility, its oral bioavailability is relatively low, limiting its therapeutical effectiveness. It is crucial to enhance the dissolution and the oral bioavailability of NDNB. In this study, we focused on the preparation of amorphous solid dispersions (ASD) using hot melt extrusion (HME). The formulation employed Kollidon® VA64 (VA64) as the polymer matrix, blended with the NDNB at a ratio of 9:1. HME was conducted at temperatures ranging from 80°C to 220°C. The successful preparation of ASD was confirmed through various tests including polarized light microscopy (PLM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). The in-vitro cumulative release of NDNB-ASD in 2h in a pH 6.8 medium was 8.3-fold higher than that of NDNB (p < 0.0001). In a pH 7.4 medium, it was 10 times higher (p < 0.0001). In the in-vivo pharmacokinetic experiments, the area under curve (AUC) of NDNB-ASD was 5.3-fold higher than that of NDNB and 2.2 times higher thanthat of commercially available soft capsules (Ofev®) (p < 0.0001). There was no recrystallization after 6months under accelarated storage test. Our study indicated that NDNB-ASD can enhance the absorption of NDNB, thus providing a promising method to improve NDNB bioavailability in oral dosages.

Sweeteners Show a Plasticizing Effect on PVP K30-A Solution for the Hot-Melt Extrusion of Fixed-Dose Amorphous Curcumin-Hesperetin Solid Dispersions.

The co-administration of curcumin and hesperetin might be beneficial in terms of neuroprotective activity; therefore, in this study, we attempted to develop a fixed-dose formulation comprising these two compounds in an amorphous state. The aim of obtaining an amorphous state was to overcome the limitations of the low solubility of the active compounds. First, we assessed the possibility of using popular sweeteners (erythritol, xylitol, and sorbitol) as plasticizers to reduce the glass transition temperature of PVP K30 to prepare the polymer-excipient blends, which allowed the preparation of amorphous solid dispersions via hot-melt extrusion at a temperature below the original glass transition of PVP K30. Erythritol proved to be the superior plasticizer. Then, we focused on the development of fixed-dose amorphous solid dispersions of curcumin and hesperetin. Powder X-ray diffraction and thermal analysis confirmed the amorphous character of dispersions, whereas infrared spectroscopy helped to assess the presence of intermolecular interactions. The amorphous state of the produced dispersions was maintained for 6 months, as shown in a stability study. Pharmaceutical parameters such as dissolution rate, solubility, and in vitro permeability through artificial membranes were evaluated. The best improvement in these features was noted for the dispersion, which contained 15% of the total content of the active compounds with erythritol used as the plasticizer.

Hydrolysis of Cellulose Acetate Phthalate and Hydroxypropyl Methylcellulose Phthalate in Amorphous Solid Dispersions

The preparation of amorphous solid dispersions (ASDs) represents a promising strategy for addressing the solubility limitations of poorly soluble drugs, facilitating enhanced absorption. Acidic polymers such as cellulose acetate phthalate (CAP) and hydroxypropyl methylcellulose phthalate (HPMCP) have emerged as effective carriers for ASDs. Although the hydrolytic degradation of these polymers has been documented, its impact on the stability of ASDs has not been systematically investigated. This research aimed to explore the potential hydrolysis of CAP and HPMCP and how it influences the stability of ASDs containing ketoconazole (KTZ), at drug loadings of 10 % and 50 %. Our study utilized thermal analysis, infrared spectroscopy, and evaluations of physical and chemical stability. The results revealed that although KTZ remained physically stable in all ASDs over a 60-day period under various stability conditions, the emergence of crystalline phthalic acid (PA), a byproduct of polymer hydrolysis, was observed at elevated temperatures and relative humidity levels. The acidic microenvironment fostered by the release of PA further catalyzed drug chemical degradation. This study underscores the susceptibility of CAP and HPMCP to hydrolytic degradation, highlighting the inherent risk of PA-induced drug degradation, particularly for acid-labile compounds. These insights into the understanding of polymer hydrolysis in ASDs pave the way for the development of targeted approaches to safeguard drug stability and optimize pharmaceutical formulations for enhanced bioavailability, efficacy, and safety.

Ternary solid dispersions of lacidipine: Enhancing dissolution and supersaturation maintenance through strategic formulation optimization

The study aimed to address the challenges related to insufficient dissolution and maintenance of supersaturation in binary solid dispersions. Lacidipine, categorized as a BCS class II drug, was employed as the model drug. A systematic screening of excipients was conducted to determine the most effective carriers for the formulations of the ternary solid dispersions, utilizing the solvent transfer method and equilibrium solubility measurements. Both binary and ternary solid dispersions were prepared via spray drying, and comprehensive physicochemical characterization confirmed the successful preparation of amorphous solid dispersions. In vitro dissolution tests, the ternary solid dispersion exhibited marked superiority over the binary solid dispersion in dissolution and maintenance of supersaturation. Furthermore, an exploration into the factors influencing the stability of ternary solid dispersions revealed their robust resistance under light-protected, room-temperature, and desiccated conditions. The formation of intermolecular hydrogen bonding within the molecules of the ternary solid dispersions significantly enhanced drug solubility and system stability. Strategic formulation optimization, coupled with judicious selection of suitable carrier types and ratios, may serve as a promising approach for designing supersaturated drug delivery systems.

Hot "Dissolving" Extrusion of Lurasidone with Natural Liquid Small Molecule for Amorphous Solid Dispersion Based Self-Assembled Submicron Emulsion.

Nowadays, ≈90% of new drug candidates under development are poorly bioavailable due to their low solubility and/or permeability. Herein, a natural liquid small molecule trans-anethole (TA) is introduced into the drug-polymer system lurasidone (LUS)-poly (1-vinylpyrrolidone-co-vinyl acetate) (VA64), notably improving the compatibility of components for the successful preparation of amorphous solid dispersion (ASD) and facilitating the formation of self-emulsifying drug delivery system (SEDDS) during dissolution. LUS-TA-VA64 ASD shows enhanced supersaturation with a long maintenance time of at least 24 h over pure LUS. The strong non-covalent force between VA64 (as emulsifier) and TA (as oil phase)/ water promotes the self-assembly of submicron emulsion and ensures its stability for at least 10 h. Compared to the commercial salt form of LUS, the ASD shows twofold increase in peak plasma concentration (Cmax ) and area under plasma concentration-time profiles (AUC), 1.5-fold increase in peak time (Tmax ), and twofold decrease in AUC-based coefficient of variation (CV) (59%→26%) after a single oral dose to a rabbit.

Novel Applications of Hot Melt Extrusion Technology

Hot melt extrusion (HME) technology was introduced to pharmaceuticals in the 1970s for manufacturing and product development. Since then, there were several developments in HME technology to utilize it effectively for the manufacturing of pharmaceuticals. Though the primary purpose of HME technology remains to be solubility enhancement through the preparation of amorphous solid dispersions, it also has various other applications like dry granulation, abuse-deterrent formulation, continuous manufacturing, film preparation, implants, sustained release formulations, etc. The purpose of this review article is to consolidate the information related to applications of HME technology in the pharmaceutical industry.&#x0D; Keywords: Hot melt extrusion, poorly soluble drugs, continuous manufacturing, solid orals, and applications.

Selection of appropriate dapsone and poly(1-vinylpyrrolidone-co-vinyl acetate) ratios for the preparation of amorphous solid dispersions

Drug-polymer miscibility is a critical requirement for the efficient design and development of amorphous solid dispersions. The objective of the current study was to determine the miscibility between dapsone (DAP) and poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP-VA) through theoretical and experimental approaches, including the use of a thermodynamic phase diagram and Gibbs free energy of mixing. In the theoretical study, the difference in the solubility parameter between the DAP and PVP-VA was 2.74, the interaction parameter was 0.50, and the distance between the drug and polymer in the Bagley plot was 2.60. Hence, all these theoretical parameters favour the miscibility between DAP and PVP-VA. Melting point depression study (through thermal analysis) and Flory-Huggins theory were utilized for the practical determination of drug-polymer miscibility, where the interaction parameter was positive, suggesting limited miscibility. The obtained thermodynamic phase diagram and Gibbs free energy of mixing plot can provide an indication for the selection of appropriate drug-polymer ratios in stable and metastable zones and the optimum processing temperature required for the preparation of amorphous solid dispersions.

Release Enhancement by Plasticizer Inclusion for Amorphous Solid Dispersions Containing High Tg Drugs.

Plasticizers are commonly used in the preparation of amorphous solid dispersions (ASDs) with the main goal of aiding processability; however, to the best of our knowledge, the impact of plasticizers on drug release has not been explored. The goal of this study was to evaluate diverse plasticizers, including glycerol and citrate derivatives, as additives to increase the drug loading where good drug release could be achieved from copovidone (PVPVA)-based dispersions, focusing on high glass transition (Tg) drugs, atazanavir (ATZ) and ledipasvir (LED). ASDs were prepared using the high Tg compounds, atazanavir (ATZ) and ledipasvir (LED), as model drugs. Release was evaluated using surface normalized dissolution testing. Differential scanning calorimetry was used to measure glass transition temperature and water vapor sorption was performed on select samples. The presence of a plasticizer at 5% w/w for ATZ and 10% w/w for LED ASDs, led to improved drug release. For ATZ ASDs, in the absence of plasticizer, release was very poor at drug loadings of 10% w/w and above. Good release was obtained for plasticized ASDs up to a drug loading of 25%. The corresponding improvement for LED was from 5 to 20% DL. Interestingly, for a low Tg compound, ritonavir, relatively smaller improvements in release as a function of drug loading were achieved through plasticizer incorporation. The use of plasticizers represents a potential new strategy to increase drug loading in ASDs for high Tg compounds with a low tendency to crystallize and may help improve a major limitation of ASD formulations, namely the high excipient burden.

Application of a three-fluid nozzle for the preparation of amorphous solid dispersions

In this work, the manufacture of amorphous solid dispersions of poorly water-soluble carbamazepine using a laboratory spray drying setup with a three-fluid nozzle and two separate liquid feed solutions of (a) the active and (b) the polymeric excipient (copovidone or basic butylated methacrylate copolymer) was investigated and compared to a traditional two-fluid nozzle setup. Results show that particles with the desired drug content were manufactured using the three-fluid nozzle setup. Amorphous solid dispersion could be obtained up to a drug load of 50% (w/w) processing solutions with miscible solvents and copovidone as polymer. Higher active concentrations, the use of immiscible solvents or switching of the capillaries led to a substantial crystallization of carbamazepine as seen in XRD and DSC analysis. The polymorphic form IV of carbamazepine was formed in the presence of copovidone at high solid concentrations of the liquid feed.

Preparation and Evaluation of Amorphous Solid Dispersions for Enhancing Luteolin's Solubility in Simulated Saliva.

Luteolin (LUT), a bioactive flavonoid, possesses various pharmacological properties, including antioxidant, antimicrobial, anti-allergic, cardio-protective, and anti-cancer activity. Among them, LUT's administration for the treatment of periodontal disease is very promising. However, its low water solubility magnifies the challenge of formulating LUT into an effective dosage form. In this vein, the aim of the present study examines the preparation of amorphous solid dispersions (ASD) for the solubility improvement of LUT in saliva. At first, the physicochemical properties of the active pharmaceutical ingredient (API) were studied before the selection of the most suitable ASD matrix/carrier. For this reason, six commonly used polymeric ASD matrix/carriers (namely, povidone, PVP; copovidone, coPVP; hydroxypropyl cellulose, HPC-SL; hydroxypropyl methyl cellulose acetate succinate, HPMC-AS; Eudragit® RS, Eud-RS; and Soluplus®, SOL) were screened via the film casting method, as to whether they could suspend the drug's recrystallization. The most promising matrix/carriers were then evaluated, based on their ability to inhibit LUT's precipitation after its solubilization, via the solvent shift method. Based on both screening methods, it was determined that PVP was the most promising matrix/carrier for the preparation of LUT's ASDs. Hence, in a further step, after the successful testing of components' miscibility, LUT-PVP ASDs were prepared via the solvent evaporation method. These systems (examined via powder X-ray diffractometry, pXRD) showed full API amorphization immediately after preparation and excellent physical stability (since they were stable after 3 months of storage). The study of LUT-PVP ASD's ATR-FTIR (Attenuated Total Reflectance-Fourier Transform Infrared) spectra demonstrated strong H-bonds between the molecules of the drug and the matrix/carrier, while molecular dynamics (MD) simulations were able to shed light on these drug-matrix/carrier interactions, at a molecular level. Finally, in vitro dissolution studies in simulated saliva proved that the prepared ASDs were able to significantly enhance LUT's dissolution profile. Hence, according to findings of the present work, the preparation of LUT-ASDs utilizing PVP as the polymeric matrix/carrier is regarded as a highly promising technique for the improvement of API's solubility in the oral cavity.

Embedding of Poorly Water-Soluble Drugs in Orodispersible Films-Comparison of Five Formulation Strategies.

The poor bioavailability of many newly developed active pharmaceutical ingredients (APIs) poses a major challenge in formulation development. To overcome this issue, strategies such as the preparation of amorphous solid dispersions (ASDs), and the application of the APIs in lipid nanocarriers or the wet-milling of the substances into nanoparticles have been introduced. In addition to an efficient formulation strategy, a dosage form that is accepted by all patients is also of great importance. To enable a simple application of the oral dosage form for all patients, orodispersible films (ODFs) are a very promising delivery platform for the APIs because the films directly disintegrate in the mouth. In this study, two poorly water-soluble APIs, fenofibrate and naproxen, were formulated using five different formulation strategies and then embedded in ODFs. It was found that the deliverable amount of API with one ODF highly depends on the formulation strategy as well as the physicochemical properties of the formulated API. The most promising film formulations were ASD-ODFs as well as films with API-loaded lipid nanoemulsions. Both showed a reduction of the dissolution time of the APIs from the ODF compared to an ODF with unformulated API micro particles. In addition, short disintegration times were achieved, although the mechanical film properties were slightly worse compared to the API-free film formulation.

Evaluation of Lapatinib-Loaded Microfibers Prepared by Centrifugal Spinning.

Lapatinib (Lap) is a lypophilic drug frequently used in cancer treatment; however, due to its limited solubility and permeability, achieving therapeutic dose through oral administration proves to be a challenge. There are various methods for enhancing the solubility of Lap and other similar drugs, one being the preparation of amorphous solid dispersions (ASD). In this study, a Lap-loaded polyvinylpyrrolidone (PVP) fiber mat was created with centrifugal spinning from a PVP/Lap solution in dimethyl formamide and ethanol. The production rate was 12.2 g/h dry fibers, and the fibers had an average thickness of 2.55 ± 0.92 μm. In the differential scanning calorimetry (DSC) thermogram of the fiber mat, the melting peak of the crystalline Lap was not visible, suggesting that Lap was in an amorphous state. A dissolution study was carried out in 0.2 M phosphate buffer saline solution at 37 °C. UV spectrophotometry data indicated that in the sample containing the fiber mat, the Lap concentration was 332 μg/mL (66%) in 10 min, decreasing to 227 μg/mL by 45 min. Meanwhile the crystalline Lap formed a 30-40 μg/mL (6-8%) solution in 5 min, maintaining that concentration. We conclude that centrifugal spinning can be an effective and easy method to produce ASDs.

Preparation and Evaluation of Siderol Amorphous Solid Dispersions: Selection of Suitable Matrix/Carrier.

The present study investigates the preparation of amorphous solid dispersions (ASD) for the ent-kaurane diterpenoid siderol (SDR). Initially, evaluation of the pure drug (isolated from Sideritis scardica) revealed that the API is a non-stable glass former, and hence the selection of a suitable ASD's matrix/carrier needs special attention. For this reason, four commonly used polymers and copolymers, namely poly(vinylpyrrolidone), copovidone, hydroxypropyl cellulose, and Soluplus® (SOL), were screenedviafilm casting and crystal growth rate measurements. Amongst them, SOL showed the highest SDR's crystal growth rate reduction, and, since it was also miscible with the drug, it was selected for further testing. In this direction, SDR-SOL ASDs were successfully preparedviamelt-quench cooling. These formulations showed full API amorphization, while good physical stability (i.e., a stable SDR amorphous dispersions) were obtained after storage for several months. Finally, evaluation of molecular interactions (with the aid of ATR-FTIR spectroscopy) showed strong H-bonds between SOL and SDR, while the use of molecular dynamics (MD) simulations unraveled the nature of these interactions. Therefore, based on the findings of the present work, SOL seems to be an appropriate matrix/carrier for the preparation of SDR ASDs, although further studies are needed in order to explore its full potentials.

The impact of the size of acetylated cyclodextrin on the stability of amorphous metronidazole

Modified oligosaccharides with cyclic topology seem to be promising excipients for the preparation of Amorphous Solid Dispersions (ASDs), especially with those Active Pharmaceutical Ingredients (APIs), which have a strong crystallization tendency from the amorphous/glassy state. Herein, the usefulness of two acetylated cyclodextrins (ac-α-CD and ac-β-CD) with various molecular weights (Mw) as stabilizers for the supercooled metronidazole (Met) has been discussed. X-ray diffraction (XRD) studies carried out on Met-acCDs mixtures (prepared in molar ratios from 1:2 to 5:1) showed that the system with ac-α-CD containing the highest amount of API (5:1 m/m) crystallizes immediately after preparation, whereas all Met-ac-β-CD ASDs remain stable. What is more, long-term XRD measurements confirmed that the Met-ac-α-CD 2:1 m/m system crystallizes after 100 days of storage in contrast to the same system containing ac-β-CD. The non-isothermal calorimetric data revealed that the activation barrier for crystallization (Ecr) in ASDs with the oligosaccharide having a greater Mw (i.e., composed of seven acGLU molecules) is slightly higher. Finally, to explain the differences in behavior between the mixtures with both acCDs, infrared studies, DFT calculations and Molecular Dynamics simulations were performed. All methods excluded the scenario of API incorporation inside the acCDs’ core. On the other hand, obtained results suggested that in comparison to ac-α-CD, the greater amount of Met molecules might be bounded on the outside surface of ac-β-CD. Therefore, this modified saccharide is a better stabilizer of the examined API.

Preparation of Azithromycin Amorphous Solid Dispersion by Hot-Melt Extrusion: An Advantageous Technology with Taste Masking and Solubilization Effects.

Azithromycin (AZI) is one of the most commonly used macrolide antibiotics in children, but has the disadvantages of a heavy bitter taste and poor solubility. In order to solve these problems, hot-melt extrusion (HME) was used to prepare azithromycin amorphous solid dispersion. Preliminary selection of a polymer for HME was conducted by calculating Hansen solubility parameter to predict the miscibility of the drug and polymer. Eudragit® RL PO was chosen as the polymer due to its combination of taste-masking effect and dissolution. Moreover, the solubility was improved with this polymer. Design of experiments (DoE) was used to optimize the formulation and process, with screw speed, extrusion temperature, and drug percentage as independent variables, and content, dissolution, and extrudates diameter as dependent variables. The optimal extrusion parameters were obtained as follows: temperature—150 °C; screw speed—75 rpm; and drug percentage—25%. Differential scanning calorimetry (DSC) and Powder X-ray Diffraction (PXRD) studies of the powdered solid dispersions showed that the crystalline AZI transformed into the amorphous form. Fourier transform infrared spectroscopy (FTIR) results indicated that the formation of a hydrogen bond between AZI and the polymer led to the stabilization of AZI in its amorphous form. In conclusion, this work illustrated the importance of HME for the preparation of amorphous solid dispersion of AZI, which can solve the problems of bitterness and low solubility. It is also of great significance for the development of compliant pediatric AZI preparation.

Study on the Effect of Polymer Excipients on the Dispersibility, Interaction, Solubility, and Scavenging Reactive Oxygen Species of Myricetin Solid Dispersion: Experiment and Molecular Simulation.

Although the preparation of amorphous solid dispersions can improve the solubility of crystalline drugs, there is still a lack of guidance on the micromechanism in the screening and evaluation of polymer excipients. In this study, a particular method of experimental characterization combined with molecular simulation was attempted on solubilization of myricetin (MYR) by solid dispersion. According to the analysis of the dispersibility and hydrogen-bond interaction, the effectiveness of the solid dispersion and the predicted sequence of poly(vinyl pyrrolidone) (PVP) > hypromellose (HPMC) > poly(ethylene glycol) (PEG) as the polymer excipient were verified. Through the dissolution, cell viability, and reactive oxygen species (ROS)-level detection, the reliability of simulation and micromechanism analysis was further confirmed. This work not only provided the theoretical guidance and screening basis for the miscibility of solid dispersions from the microscopic level but also served as a reference for the modification of new drugs.

Optimization and evaluation of resveratrol amorphous solid dispersions with a novel polymeric system.

The preparation of amorphous solid dispersions using polymers is a commonly used formulation strategy for enhancing the solubility of poorly water-soluble drugs. However, a single polymer often does not bring significantly enhance the solubility or amorphous stability of a poorly water-soluble drug. We found an application of a unique and novel binary polymeric blend in the preparation of solid dispersions. The main purpose of this study is to optimize and evaluate resveratrol (Res) amorphous solid dispersions with a novel polymeric system of poly (vinyl pyrrolidone) (PVP) and carboxymethyl chitosan (CMCS). The influence of three different release factors, the ratio of CMCS to the polymer mixture (CMCS% = X1), the ratio of Res to the polymer mixture (Res% = X2) and the surfactant (Tween 80 = X3), on the characteristics of released Res at various times (Q5 and Q30) was investigated. The computer optimization and contour plots were used to predict the levels of the independent variables as X1 = 0.17, X2 = 0.10 and X3 = 2.94 for maximized responses of Q5 and Q30. Fourier transform infrared spectroscopy (FTIR) results revealed that each polymer formed hydrogen bonds with Res. The solid performance and physical stability of the optimized ternary dispersions were studied with scanning electron microscopy (SEM), powder X-ray diffraction (XRD), modulated differential scanning calorimetry (MDSC) and dissolution testing. SEM, XRD and MDSC analysis demonstrated that the Res was amorphous, and MDSC showed no evidence of phase separation during storage. Dissolution testing indicated a more than fourfold increase in the apparent solubility of the optimized ternary dispersions, which maintained high solubility after 90 days. In our research, we used CMCS as a new carrier in combination with PVP, which not only improved the in vitro dissolution of Res but also had better stability.

Exploration of theoretical and practical evaluation on Kollidon®SR matrix mediated amorphous filament extrusion of norfloxacin by melt extrusion

The selection of an appropriate polymer for the preparation of amorphous solid dispersions via hot-melt extrusion (HME) deals with the study of various solid-state properties of drugs and polymers. Hence, before going to HME, it is necessary to have appropriate knowledge of drug-polymer miscibility, drug-polymer interactions, and Gibb's free energy of mixing for the respective drug-polymer system. In the present work, we evaluated the miscibility and interaction parameters between norfloxacin (NOR) and Kollidon®SR Powder (KSR-P). The solubility parameter approach, based on theoretical calculations, was performed as a preliminary step for the prediction of miscibility between NOR and KSR-P. A theoretical and experimental approach was used as a validation tool using Flory-Huggin's interaction parameter value determined using the melting point depression method. The effect of NOR loading on the interaction parameter was systemically predicted to construct a thermodynamic phase diagram and Gibb's free energy of mixing for the NOR and KSR-P binary systems for the preparation of amorphous filament extrudate. A temperature-composition phase diagram was used to predict the processing temperature at the respective NOR loading to obtain a homogenous amorphous extrudate. Further, the obtained extrudate was evaluated through dimension studies, NOR assay, DSC, XRD, ATR analysis, and release behaviour.

Miscibility and thermal properties of poly(vinylpyrrolidone-vinyl acetate)/lamivudine and tenofovir binary blends prepared by hot melt extrusion

Preparation of amorphous solid dispersions (ASD) by hot melt extrusion (HME) of poly(vinylpyrrolidone-vinyl acetate) (Kollidon) and the active pharmaceutical ingredients (API) Lamivudine (3TC) and Tenofovir Disoproxyl Fumarate (TDF) was investigated aiming to study their miscibility and thermal behavior. These two drugs are currently used as drugs in first line treatment of patients with Acquired Immunodeficiency Syndrome (AIDS). In order to predetermine parameters for extrusion and the maximum concentration of API to be used without any recrystallization, binary blends were first processed in the mixing chamber at 130°C using a roller type rotor at 10, 20 and 30 rpm for 7 min, giving rise to ASD of both API, at least up to 20 wt% of the drug. Both 3TC and TDF were then extruded individually with Kollidon in a single screw extruder. HME produced ASD with high concentration of both Kollidon/API combinations, being part of the API soluble in the polymer matrix. From HME, Kollidon/3TC forms ASD in concentration up to 50 wt%, but from 30 wt% 3TC, the ASD has no time stability, showing recrystallization in less than 5 months, while the Kollidon/TDF system forms ASD up to 30 wt% of TDF, but it has aging stability inferior to 4 months.