Hot melt extrusion for amorphous solid dispersions: temperature and moisture activated drug-polymer interactions for enhanced stability.

Hot melt extrudates (HMEs) of indomethacin (IND) with Eudragit EPO and Kollidon VA 64 and those of itraconazole (ITZ) with HPMCAS-LF and Kollidon VA 64 were manufactured using a Leistritz twin screw extruder. The milled HMEs were stored at controlled temperature and humidity conditions. The samples were collected after specified time periods for 3 months. The stability of amorphous HMEs was assessed using moisture analysis, thermal evaluation, powder X-ray diffraction, FTIR, HPLC, and dissolution study. In general, the moisture content increased with time, temperature, and humidity levels. Amorphous ITZ was physically unstable at very high temperature and humidity levels, and its recrystallization was detected in the HMEs manufactured using Kollidon VA 64. Although physical stability of IND was better sustained by both Eudragit EPO and Kollidon VA 64, chemical degradation of the drug was identified in the stability samples of HMEs with Eudragit EPO stored at 50 °C. The dissolution rates and the supersaturation levels were significantly decreased for the stability samples in which crystallization was detected. Interestingly, the supersaturation was improved for the stability samples of IND:Eudragit EPO and ITZ:HPMCAS-LF, in which no physical or chemical instability was observed. This enhancement in supersaturation was attributed to the temperature and moisture activated electrostatic interactions between the drugs and their counterionic polymers.

Supersolubilization and amorphization of a model basic drug, haloperidol, by interaction with weak acids.

PURPOSE: To present a novel approach of greatly enhancing aqueous solubility of a model weakly basic drug, haloperidol, by using weak acids that would not form salts with the drug and to attain physically stable form of amorphous drug by drying such aqueous solutions. METHOD: Aqueous solubility of haloperidol in presence of increasing concentrations of four different weak organic acids (malic, tartaric, citric, fumaric) were determined. Several concentrated aqueous solutions with differing drug-to-acid molar ratios were dried in vacuum oven, and dried materials were characterized by DSC, powder XRD, dissolution testing, and stability study. RESULT: Acids were selected such that they would not form salts with haloperidol. Haloperidol solubility increased greatly with increased concentrations of malic, tartaric and citric acids, reaching >300 mg/g of solution. In contrast to the haloperidol HCl aqueous solubility of 4 mg/g, this may be called supersolubilization. Fumaric acid did not cause such solubilization as it had low water solubility. Dried solids formed dispersions of amorphous haloperidol in acids that were either amorphous or partially crystalline. Amorphous haloperidol was physically stable and had better dissolution rate than HCl salt. CONCLUSION: A novel method of drug solubilization in aqueous media by acid-base interaction is presented. Physically stable amorphous systems of drugs may also be prepared by using this organic solvent-free approach.

Understanding and optimizing the dual excipient functionality of sodium lauryl sulfate in tablet formulation of poorly water soluble drug: wetting and lubrication.

PURPOSE: To evaluate and optimize sodium lauryl sulfate (SLS) and magnesium stearate (Mg.St) levels, with respect to dissolution and compaction, in a high dose, poorly soluble drug tablet formulation. METHODS: A model poorly soluble drug was formulated using high shear aqueous granulation. A D-optimal design was used to evaluate and model the effect of granulation conditions, size of milling screen, SLS and Mg.St levels on tablet compaction and ejection. The compaction profiles were generated using a Presster(©) compaction simulator. Dissolution of the kernels was performed using a USP dissolution apparatus II and intrinsic dissolution was determined using a stationary disk system. RESULTS: Unlike kernels dissolution which failed to discriminate between tablets prepared with various SLS contents, the intrinsic dissolution rate showed that a SLS level of 0.57% was sufficient to achieve the required release profile while having minimal effect on compaction. The formulation factors that affect tablet compaction and ejection were identified and satisfactorily modeled. The design space of best factor setting to achieve optimal compaction and ejection properties was successfully constructed by RSM analysis. CONCLUSIONS: A systematic study design helped identify the critical factors and provided means to optimize the functionality of key excipient to design robust drug product.

Influence of plasticizer type and level on the properties of Eudragit S100 matrix pellets prepared by hot-melt extrusion.

Matrix-type pellets with controlled-release properties may be prepared by hot-melt extrusion applying a single-step, continuous process. However, the manufacture of gastric-resistant pellets is challenging due to the high glass transition temperature of most enteric polymers and an unacceptably high, diffusion-controlled drug release from the matrix during the acidic phase. The objective was to investigate the influence of three plasticizers (triethyl citrate, methylparaben and polyethylene glycol 8000) at two levels (10% or 20%) on the properties of hot-melt extruded Eudragit S100 matrix pellets. Extrusion experiments showed that all plasticizers produced similar reductions in polymer melt viscosity. Differential scanning calorimetry and powder X-ray diffraction demonstrated that the solid state plasticizers were present in the amorphous state. The drug release in acidic medium was influenced by the aqueous solubility of the plasticizer. Less than 10% drug was released after 2 h at pH 1.2 when triethyl citrate or methylparaben was used, independent of the plasticizer level. Drug release at pH 7.4 resulted from polymer dissolution and was not influenced by low levels of plasticizer, but increased significantly at the 20% level. Mechanical testing by diametral compression demonstrated the high tensile strength of the hot-melt extruded pellets that decreased when plasticizers were present.

Functional performance of silicified microcrystalline cellulose versus microcrystalline cellulose: a case study.

BACKGROUND: During the development of a tablet dosage form of an investigational compound, R411, several aspects were identified as critical quality attributes that required optimization. The use of nonsolvent processing prevented the moisture-induced physical changes in the drug product but presented manufacturing challenges related to sticking during compression and slowdown in dissolution after storage at stress conditions. AIM: The aim of this study was to evaluate silicified microcrystalline cellulose (SMCC), microcrystalline cellulose (MCC), and physical mixture of MCC-colloidal silicon dioxide (MCC/CSD at 98:2 ratio) as extragranular compression aids to address the processing and dissolution stability issues of this formulation. METHODS: The compactibility and stickiness upon compression over extended period of time as well as the dissolution of R411 formulations incorporating the aforementioned compression aids were investigated. In addition, the water sorption/desorption properties of these compression aids were determined. RESULTS: All formulations showed comparable compactibility irrespective of the compression aid used. Nevertheless, MCC alone or in a physical mixture with CSD showed sticking of the lower punches, whereas SMCC resulted in clean punch surface during extended compression runs. Furthermore, the three compression aids were compared for their effect on dissolution stability after storage at stress conditions. The formulations containing SMCC provided superior dissolution stability over the other compression aids evaluated in the study. CONCLUSIONS: Novel functionalities of SMCC are presented in terms of sticking prevention while having the most beneficial effect on dissolution stability in R411 formulation.

Influence of an acrylic polymer blend on the physical stability of film-coated theophylline pellets.

The purpose of this study was to investigate the physical stability of a coating system consisting of a blend of two sustained release acrylic polymers and its influence on the drug release rate of theophylline from coated pellets. The properties of both free films and theophylline pellets coated with the polymer blend were investigated, and the miscibility was determined via differential scanning calorimetry. Eudragit RS 30 D was plasticized by the addition of Eudragit NE 30 D, and the predicted glass transition temperature (T(g)) of the blend was similar to the experimental values. Sprayed films composed of a blend of Eudragit NE 30 D/Eudragit RS 30 D (1:1) showed a water vapor permeability six times greater than films containing only Eudragit NE 30 D. The presence of quaternary ammonium functional groups from the RS 30 D polymer increased the swellability of the films. The films prepared from the blend exhibited stable permeability values when stored for 1 month at both 25 degrees C and 40 degrees C, while the films which were composed of only Eudragit NE 30 D showed a statistically significant decrease in this parameter when stored under the same conditions. Eudragit NE 30 D/Eudragit RS 30 D (1:1)-sprayed films decreased in elongation from 180% to 40% after storage at 40 degrees C for 1 month, while those stored at 25 degrees C showed no change in elongation. In coated pellets, the addition of Eudragit RS 30 D to the Eudragit NE 30 D increased the theophylline release rate, and the pellets were stable when stored at 25 degrees C for a period of up to 3 months due to maintenance of the physico-mechanical properties of the film. Pellets stored at 40 degrees C exhibited a decrease in drug release rate over time as a result of changes in film physico-mechanical properties which were attributed to further coalescence and densification of the polymer. When the storage temperature was above the T(g) of the composite, instabilities in both drug release rate and physical properties were evident. Stabilization in drug release rate from coated pellets could be correlated with the physico-mechanical stability of the film formulation when stored at temperatures below the T(g) of the polymer.

Stabilization of low glass transition temperature indomethacin formulations: impact of polymer-type and its concentration.

The objectives of this study were to formulate and stabilize amorphous formulation of low T(g) drug (Indomethacin, INM) with selected polymers and compare these formulations based on solubility and dissolution rate studies. Eudragit EPO (EPO), Polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), and Polyvinylpyrrolidone K30 (PVPK30) were selected as hydrophilic polymers. The melt extrudates were characterized using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), intrinsic dissolution rate and solubility studies. The formation of single-phase amorphous form was confirmed by DSC and PXRD. The melt extrudates showed a higher intrinsic dissolution rate (IDR), and solubility compared to the pure drug. The amorphous drug in solid solutions with EPO, PVP-VA, and PVPK30 showed tendency to revert back to crystalline form. However, the rate of reversion was dependent on the nature and concentration of the polymer. The solid solution with high ratio of EPO provided superior stabilization of the amorphous INM from crystallization. The stability of the amorphous form of INM could not be related to the glass transition temperature of the formulation as the mechanism of stabilization with EPO appears to be molecular interaction rather than immobilization. The presence of specific molecular interactions between INM and EPO was also shown by the antiplasticization effect.

Evaluation of solid state properties of solid dispersions prepared by hot-melt extrusion and solvent co-precipitation.

The solid state properties of solid dispersions of Compound A in hypromellose acetate succinate (HPMC-AS) prepared by hot-melt extrusion (HME) and solvent co-precipitation (CP) processes were evaluated using powder X-ray diffractometry (PXRD), thermal analysis, optical microscopy, scanning electron microscopy (SEM), FT-IR and Raman spectroscopy, water vapor sorption analyzer, and surface area by BET. PXRD indicated that both processes converted the crystalline drug into amorphous solid dispersions with a glass transition temperature around 104-107 degrees C and both products have similar spectroscopic and hygroscopic properties. The two products have similar true densities; however, the CP product is more porous and has a larger specific surface area than the HME product, as indicated by the BET results and SEM micrographs. Dissolution study using USP apparatus 2 showed that the CP product had a faster dissolution profile, but slower intrinsic dissolution rate than the HME product. The two products have acceptable physical stability after storage in 40 degrees C/75% RH chamber for 3 months. However, the HME product is more stable than the CP product in aqueous suspension formulation.

Citric acid monohydrate as a release-modifying agent in melt extruded matrix tablets.

Incomplete drug release and particle size-dependent dissolution performance can compromise the quality of controlled release matrix systems. The objective of the current study was to investigate the ability of citric acid monohydrate (CA MH) to enhance the release of diltiazem hydrochloride from melt extruded Eudragit RS PO tablets and to eliminate drug particle size effects. Preformulation studies demonstrated the thermal stability of all components, drug insolubility in the polymer but miscibility with the CA MH. Tablets with either constant polymer levels or constant drug-to-polymer ratios and containing different drug particle size fractions and increasing amounts of CA MH were manufactured by melt extrusion and characterized by dissolution testing, powder X-ray diffraction and scanning electron microscopy. The addition of CA MH to the formulation promoted the thermal processibility and matrix integrity by plasticization of the polymer. The drug release from systems with constant drug-to-polymer ratio was significantly increased when CA MH was added as a result of enhanced pore formation. Particle size effects were eliminated when large amounts of CA MH were used due to the loss of drug crystallinity. Matrix tablets with CA MH furthermore showed a faster and more complete drug release compared to systems with drug only or alternative pore formers (sucrose, NaCl, or PEG 3350). The enhanced drug release was attributed to the amorphous character of the soluble components, improved drug dispersion in the plasticized polymer along with increased polymer permeability. In summary, CA MH promoted the miscibility between the drug and Eudragit RS PO during hot-melt extrusion, resulting in the extrusion of an amorphous system with improved dissolution characteristics.

Selection of Solid-State Plasticizers as Processing Aids for Hot-Melt Extrusion.

The objective of the study was to select solid-state plasticizers for hot-melt extrusion (HME) process. The physical and mechanical properties of plasticizers, in selected binary (polymer:plasticizer) and ternary (active pharmaceutical ingredient:polymer:plasticizer) systems, were evaluated to assess their effectiveness as processing aids for HME process. Indomethacin and Eudragit® E PO were selected as model active pharmaceutical ingredient and polymer, respectively. Solubility parameters, thermal analysis, and rheological evaluation were used as assessment tools. Based on comparable solubility parameters, stearic acid, glyceryl behenate, and polyethylene glycol 8000 were selected as solid-state plasticizers. Binary and ternary physical mixtures were evaluated as a function of plasticizer concentration for thermal and rheological behavior. The thermal and rheological assessments also confirmed the miscibility predictions from solubility parameters. The understanding of thermal and rheological properties of the various mixtures helped in predicating plasticization efficiency of stearic acid, glyceryl behenate, and polyethylene glycol 8000. The evaluation also provided insight into the properties of the final product. An empirical model was also developed correlating rheological property of physical mixtures to actual HME process. Based on plasticizer efficiency, solid-state plasticizers and processing conditions can be selected for a HME process.

Citric acid as a solid-state plasticizer for Eudragit RS PO.

The use of solid-state plasticizers for the hot-melt extrusion of pharmaceutical dosage forms has been shown to be beneficial compared with liquid plasticizers. The purpose of this study was to determine the suitability of citric acid (CA) as a solid plasticizer for the preparation of Eudragit RS PO extended-release matrix systems by a melt extrusion technique. The influence of increasing levels of CA monohydrate (CA MH) or anhydrous CA in the powder blend on the extrusion process parameters (screw speed and motor load) was determined as a function of temperature. The solubility of CA MH in extruded tablets was studied by means of modulated differential scanning calorimetry (MDSC) and powder X-ray diffraction (PXRD). Films were cast from organic solutions to demonstrate the plasticizing effect of CA MH as a change in physico-mechanical properties (tensile strength, elastic modulus and elongation). The CA release from extruded tablets was studied over 12 h. The monohydrate form was found to distinctly facilitate the extrusion of Eudragit RS PO, whereas the addition of anhydrous CA to the polymer powder was less effective. This divergent behaviour in plasticization of Eudragit RS PO was attributed to the higher solubility of the monohydrate in the acrylic polymer. The plasticizing effect of the CA MH reached a plateau at 25% during hot-melt extrusion, which coincided with the solubility limit of the organic acid in the polymer as shown by MDSC and PXRD results. The CA MH increased the flexibility of Eudragit RS PO films, as demonstrated by a decrease in tensile strength and elastic modulus and an increase in elongation as a function of CA MH concentration. The dissolution of CA from the matrix tablets followed an extended-release profile, with CA MH exhibiting a faster dissolution rate than the anhydrous form. In conclusion, CA MH was found to be an effective plasticizer for Eudragit RS PO that facilitates the production of controlled-release matrix systems by hot-melt extrusion.

Improving the dissolution rate of poorly water soluble drug by solid dispersion and solid solution: pros and cons.

The solid dispersions with poloxamer 188 (P188) and solid solutions with polyvinylpyrrolidone K30 (PVPK30) were evaluated and compared in an effort to improve aqueous solubility and bioavailability of a model hydrophobic drug. All preparations were characterized by differential scanning calorimetry, powder X-ray diffraction, intrinsic dissolution rates, and contact angle measurements. Accelerated stability studies also were conducted to determine the effects of aging on the stability of various formulations. The selected solid dispersion and solid solution formulations were further evaluated in beagle dogs for in vivo testing. Solid dispersions were characterized to show that the drug retains its crystallinity and forms a two-phase system. Solid solutions were characterized to be an amorphous monophasic system with transition of crystalline drug to amorphous state. The evaluation of the intrinsic dissolution rates of various preparations indicated that the solid solutions have higher initial dissolution rates compared with solid dispersions. However, after storage at accelerated conditions, the dissolution rates of solid solutions were lower due to partial reversion to crystalline form. The drug in solid dispersion showed better bioavailability in comparison to solid solution. Therefore, considering physical stability and in vivo study results, the solid dispersion was the most suitable choice to improve dissolution rates and hence the bioavailability of the poorly water soluble drug.

Properties of hot-melt extruded tablet formulations for the colonic delivery of 5-aminosalicylic acid.

Hot-melt extruded tablets were prepared using Eudragit S 100 as the polymeric carrier to target delivery of 5-aminosalicylic acid (5-ASA) to the colon. Scanning electron microscopy, modulated differential scanning calorimetry and X-ray diffraction analysis of the hot-melt tablet extrudates demonstrated that 5-ASA remained crystalline and was homogeneously dispersed throughout the polymer matrix. A pre-plasticization step was necessary when incorporating triethyl citrate (TEC) into the formulation in order to achieve uniform mixing of the polymer and plasticizer, effectively reduce the polymer glass transition temperature (T(g)), and to lower the processing temperatures. The concentration of TEC in the extrudates not only influenced the processing temperature, but also influenced the drug release rates from the extruded tablets due to leaching of the TEC during dissolution testing. Citric acid monohydrate was found to plasticize Eudragit S 100, and when combined with TEC in the powder blend, the temperatures required for processing were reduced. Tablets containing citric acid released drug at a slower rate as a result of the suppression of polymer ionization due to a decrease in the micro-environmental pH of the tablet. The drug release profiles of the extruded tablets were found to fit both diffusion and surface erosion models.

Characterization of physico-mechanical properties of indomethacin and polymers to assess their suitability for hot-melt extrusion processs as a means to manufacture solid dispersion/solution.

The objective of the study was to characterize the physical and viscoelastic properties of binary mixtures of drug and selected polymers to assess their suitability for use in the hot-melt extrusion (HME) process as a means to improve solubility by manufacturing either solid dispersion or solid solution. Indomethacin (INM) was selected as a model drug. Based on comparable solubility parameters, the selected polymers were Eudragit EPO (EPO), polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA), polyvinylpyrrolidone K30 (PVPK30), and poloxamer 188 (P188). The various drug and polymer systems were characterized for thermal and rheological properties as a function of drug concentration to provide an insight into miscibility and processibility of these systems. From the thermal analysis studies, a single T(g) was observed for the binary mixtures of INM/EPO, INM/PVP-VA, and INM/PVPK30, indicating miscibility of drug and polymer in the given ratios. In the case of mixtures of INM/P188, two melting endotherms were observed with decreasing drug melting point as a function of polymer concentration indicating partial miscibility of drug in polymer. As part of the rheological evaluation, zero rate viscosity (eta(o)) and activation energy (E(a)) was determined for the various systems using torque rheometer at varying shear rates and temperatures. The eta(o) for binary mixtures of drug and EPO, PVP-VA and PVPK30 were found to be significantly lower as compared to pure polymer, indicating disruption of the polymer structure due to miscibility of the drug. On the other hand, INM/P188 mixtures showed a higher eta(o) compared to pure polymer indicating partial miscibility of drug and polymer. With respect to E(a), the mixtures of INM/EPO showed an increase in E(a) with increasing drug concentration, suggesting antiplasticization effect of the drug. These findings corroborate the thermal analysis results showing increase T(g) for the various binary mixtures. The mixtures of INM/PVP-VA showed a decrease in the E(a) with the increasing drug concentration suggesting a plasticization effect of the drug. The understanding of thermal and rheological properties of the various drug/polymer mixtures help established the processing conditions for hotmelt extrusion (such as extrusion temperatures and motor load) as well as provided insight into the properties of the final extrudates. Using the actual hot-melt processing, a model was developed correlating the zero rate viscosity to the motor load determined by rheological evaluation.

Solid-state plasticization of an acrylic polymer with chlorpheniramine maleate and triethyl citrate.

The influence of in situ plasticization of chlorpheniramine maleate (CPM) on Eudragit RS PO from hot-melt extruded matrix tablets, and from compressed granules prepared by thermal processing was investigated. CPM was studied as both a model drug substance and as a solid-state plasticizer for the acrylic polymer. Triethyl citrate (TEC) was incorporated into the polymer blend as a liquid plasticizer for the polymer. The influence of TEC and CPM concentration on the dissolution properties of CPM tablets was investigated. The glass transition temperature (T(g)) of the samples was determined by modulated differential scanning calorimetry (MDSC). The morphologies of the granules formed by hot-melt extrusion and hot-melt granulation processes were investigated by scanning electron microscopy. The addition of 12% TEC to the polymer reduced the T(g) by 32.5 degrees C, while the reduction in the T(g) for the same level of CPM was 16.4 degrees C. The effect of TEC levels on drug release was dependent on the tablet preparation method. At high TEC levels, the release rate of CPM decreased in tablets prepared by direct compression and tablets made from compressed granules that had been prepared by high shear hot-melt granulation. However, the CPM release rate increased from hot-melt extruded tablets with increasing blends of plasticizer in the extruded tablets. An increase in the CPM content in the tablets resulted in an increase in the drug release rate. During high shear hot-melt granulation, the model drug adhered to the polymer to form a porous discontinuous structure. Following hot-melt extrusion, the drug was distributed at a molecular level in the continuous polymeric structure. The influence of both CPM and TEC levels on the drug release rate from these polymeric drug delivery systems was shown to be a function of whether the granules or tablets were formed by either hot-melt granulation or hot-melt extrusion, as well as the plasticization effects of both TEC and CPM on the acrylic polymer.

Stability assessment of hypromellose acetate succinate (HPMCAS) NF for application in hot melt extrusion (HME).

HPMCAS is a widely used polymer in the pharmaceutical industry as an excipient. In this work, the physicochemical stability of HPMCAS was investigated for hot melt extrusion (HME) application. The reduction in zero rate viscosity (η0) of the polymer with the increase in temperature was determined using rheological evaluation prior to HME processing. The energy of activation for AS-MF determined by fitting Arrhenius model to the temperature dependent reduction in η0 was found to be slightly lower than that for the other grades of HPMCAS. Glassy yellowish HMEs were obtained using Haake Mini-Lab MicroCompounder operated at 160, 180, and 200°C and 100, 200, and 300 rpm for all the grades at each temperature. Various physicochemical properties of HPMCAS such as glass transition temperature, semi-crystalline nature, solid state functional group properties, moisture content, and solution viscosity were not significantly affected by the HME processing. The most significant change was the release of acetic and succinic acid with the increase in HME temperature and speed. The free acid content release due to HME was directly proportional to the speed at lower operating temperatures. AS-LF was found to be the most stable with the lowest increase in total free acid content even at higher HME temperature and speed. Although the dissolution time was not affected due to HME for AS-LF and AS-MF grades, it was notably increased for AS-HF, perhaps due to significant reduction of succinoyl content. In conclusion, the HME processing conditions for solid dispersions of HPMCAS should be based on the acceptance levels of free acid for the drug and the drug product.

Highly efficient miniaturized coprecipitation screening (MiCoS) for amorphous solid dispersion formulation development.

Microprecipitated bulk powder (MBP) is a novel solid dispersion technology to manufacture amorphous formulations of poorly soluble compounds that cannot be processed by spray drying or melt extrusion. An efficient high-throughput screening method has been developed to aid the selection of polymer type, drug loading and antisolvent to solvent ratio for MBP formulation development. With a 96-well platform, the miniaturized coprecipitation screening (MiCoS) includes mixing of drug and polymer in dimethylacetamide, controlled precipitation to generate MBP, filtration/washing, drying and high throughput characterization. The integrated MiCoS approach has been demonstrated with a model compound, glybenclamide. Based on the solid state stability and kinetic solubility of the MBP, hydroxypropylmethylcellulose acetate succinate polymer with 40% or lower drug loading, and antisolvent (0.01 N HCl) to solvent (dimethylacetamide) ratio of 5:1 or higher were selected to make glybenclamide MBP. MiCoS can be applied to both early and late stage formulation processing. In early stage research programs, the system can be used to enable efficacy, pharmacokinetics or mini-toxicology studies for poorly water soluble molecules using minimal amount of drug substance (2-10mg). In late stage development programs, MiCoS can be used to optimize MBP formulation by expanding the experimental design space to include additional formulation variants.

Hot melt extrusion (HME) for amorphous solid dispersions: predictive tools for processing and impact of drug-polymer interactions on supersaturation.

The processing parameters for HME have been evaluated and the impact of solid state intermolecular drug-polymer interactions on supersaturation has been investigated. Poorly water soluble drugs Indomethacin (IND), Itraconazole (ITZ), and Griseofulvin (GSF) and hydrophilic polymers - Eudragit EPO, Eudragit L-100-55, Eudragit L-100, HPMCAS-LF, HPMCAS-MF, Pharmacoat 603, and Kollidon VA-64 were selected for this study. Solubility parameters calculations (SPCs), differential scanning calorimetry (DSC), and rheological analysis of drug-polymer physical mixtures (PMs) was performed. The solid dispersions were manufactured using HME and characterized by powder X-ray diffraction (PXRD), polarized light microscopy (PLM), Fourier transform infra-red (FTIR) Spectroscopy, and dissolution study. Results obtained by DSC correlated well with SPC, showing single glass transition temperatures for all the PMs except ITZ in Eudragit EPO that depicted the highest difference in solubility parameters. The zero rate viscosity (η0) was dependent on the melting point and consequently the state of the drug in the polymer at the softening temperature. The η0 of PMs was useful to estimate the processing conditions for HME and to produce transparent glassy HMEs from most of the PMs. The amorphous conversion due to HME was confirmed by PXRD and PLM. The solid state drug-polymer interactions occurred during HME could be confirmed by FTIR analysis. Highest supersaturation could be achieved for IND, ITZ, and GSF using Eudragit EPO, HPMCAS-LF, and Eudragit L-100-55, respectively where relatively higher stretching of the carbonyl peaks was observed by FTIR. Thus, the highest dissolution rate and supersaturation of poorly water soluble drugs could be attributed to drug-polymer interactions occurred during HME.

Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process.

The present work deals with improving the solubility of vemurafenib, a practically insoluble drug, by converting it into an amorphous-solid dispersion using a solvent-controlled precipitation process. The dispersion containing vemurafenib and hypromellose acetate succinate (HPMCAS), an enteric polymer, is termed microprecipitated bulk powder (MBP), in which the drug is uniformly dispersed within the polymeric substrate. HPMCAS was found to be the most suitable polymer for vemurafenib MBP, among a series of enteric polymers based on superior physical stability and drug-release characteristics of the MBP. The MBP provided a greater rate and extent of dissolution than crystalline drug, reaching an apparent drug concentration of 28-35 µg/mL, almost 30-fold higher than solubility of crystalline drug at 1 µg/mL. The supersaturation was also maintained for more than 4 h. Upon exposure to high temperature and humidity, the MBP was destabilized, resulting in crystallization and lower dissolution rate. The control of moisture and temperature is essential to maintain the stability of the MBP. In a relative human bioavailability study, vemurafenib MBP provided a four- to fivefold increase in exposure compared with crystalline drug. Improving solubility with an amorphous-solid dispersion is a viable strategy for the development of practically insoluble compounds.

Nanoparticles in the pharmaceutical industry and the use of supercritical fluid technologies for nanoparticle production.

Poor aqueous solubility of drug candidates is a major challenge for the pharmaceutical scientists involved in drug development. Particle size reduction appears as an effective and versatile option for solubility improvement. Nanonization is an attractive solution to improve the bioavailability of the poorly soluble drugs, improved therapies, in vivo imaging, in vitro diagnostics and for the production of biomaterials and active implants. In drug delivery, application of nanotechnology is commonly referred to as Nano Drug Delivery Systems (NDDS). In this article, commercially available nanosized drugs, their dosage forms and proprietors, as well as the methods used for preparation like milling, high pressure homogenization, vacuum deposition, and high temperature evaporation were listed. Unlike the traditional methods used for the particle size reduction, supercritical fluid-processing techniques offer advantages ranging from superior particle size control to clean processing. The primary focus of this review article is the use of supercritical CO2 based technologies for small particle generation. Particles that have the smooth surfaces, small particle size and distribution and free flowing can be obtained with particular SCF techniques. In almost all techniques, the dominating process variables may be thermodynamic and aerodynamic in nature, and the design of the particle collection environment. Rapid Expansion of Supercritical Solutions (RESS), Supercritical Anti Solvent (SAS) and Particles from Gas Saturated Solutions (PGSS) are three groups of processes which lead to the production of fine and monodisperse powders. Few of them may also control crystal polymorphism. Among the aforementioned processes, RESS involves dissolving a drug in a supercritical fluid (SCF) and passing it through an appropriate nozzle. Rapid depressurization of this solution causes an extremely rapid nucleation of the product. This process has been known for a long time but its application is limited. Carbon dioxide, which is the only supercritical fluid that is preferentially used in pharmaceutical processes, is not a good solvent for many Active Pharmaceutical Ingredients (API). Various researchers have modified the RESS process to overcome its solubilizing limitations, by introducing RESOLV, RESAS, and RESS-SC. Overall, all RESS based processes are difficult to scale up. The SAS processes are based on decreasing the solvent power of a polar organic solvent in which the substrate (API & polymer of interest) is dissolved, by saturating it with carbon dioxide (CO2) at supercritical conditions. CO2 causes precipitation and recrystalization of the drug. SAS is scalable and can be applied to a wide variety of APIs and polymers. Minor modifications of basic SAS process include GAS, ASES, SAS-DEM and SAS-EM. Processes where SCF is used as an anti solvent and dispersing agent include SEDS, SAA, and A-SAIS. The mechanisms and applications of these processes were briefly discussed. In PGSS, CO2 is dissolved in organic solutions or melted compounds and it is successfully used for manufacturing drug products as well as for drying purposes. The two widely used methods, PGSSdrying and CAN-BD SCF, were also included in discussions. Among the limitations of the techniques involved, the poor solvent power of CO2, the cost and necessity of voluminous usage of the CO2 can be mentioned. There is still confusion in contribution of each variable on the particle morphology and properties regardless of the number of mechanistic studies available. The advantages of especially SAS and PGSS based techniques are the production of the nano or micro sized spherical particles with smooth surfaces and narrow particle size distribution. Regardless of its advantages, the reasons why 25 years of active research, and more than 10 years of process development could not promote the use of (SCF) technology, and produced only few commercial drug products, necessitate further evaluation of this technique.