Study the influence of formulation process parameters on solubility and dissolution enhancement of efavirenz solid solutions prepared by hot-melt extrusion: a QbD methodology.

The current study investigates the dissolution rate performance of amorphous solid solutions of a poorly water-soluble drug, efavirenz (EFV), in amorphous Soluplus® (SOL) and Kollidon® VA 64 (KVA64) polymeric systems. For the purpose of the study, various formulations with varying drug loadings of 30, 50, and 70% w/w were developed via hot-melt extrusion processing and adopting a Box-Behnken design of experiment (DoE) approach. The polymers were selected based on the Hansen solubility parameter calculation and the prediction of the possible drug-polymer miscibility. In DoE experiments, a Box-Behnken factorial design was conducted to evaluate the effect of independent variables such as Soluplus® ratio (A1), HME screw speed (A2), and processing temperature (A3), and Kollidon®VA64 ratio (B1), screw speed (B2), and processing temperature (B3) on responses such as solubility (X1 and Y1) and dissolution rate (X2 and Y2) for both ASS [EFV:SOL] and BSS [EFV:KVA64] systems. DSC and XRD data confirmed that bulk crystalline EFV transformed to amorphous form during the HME processing. Advanced chemical analyses conducted via 2D COSY NMR, FTIR chemical imaging, AFM analysis, and FTIR showed that EFV was homogenously dispersed in the respective polymer matrices. The maximum solubility and dissolution rate was observed in formulations containing 30% EFV with both SOL and KVA64 alone. This could be attributed to the maximum drug-polymer miscibility in the optimized formulations. The actual and predicted values of both responses were found precise and close to each other.

Solid crystal suspension of Efavirenz using hot melt extrusion: Exploring the role of crystalline polyols in improving solubility and dissolution rate.

Poor aqueous solubility of drugs has emerged as a major issue for pharmaceutical scientists from many decades. The current study explores the manufacture and development of a thermodynamically stabilized solid crystal suspension (SCS) of poorly water soluble drug efavirenz via hot melt extrusion. Efavirenz is a non-nucleoside reverse transcriptase inhibitor and belongs to BCS class II. The SCS was prepared using pearlitol and xylitol as a crystalline carrier. The drug-excipient blend was processed by hot melt extrusion with up to 50% (w/w) drug loading. Physico-chemical characterization of the SCS conducted via a scanning electron microscopy, differential scanning calorimetry and hot stage microscopy confirmed that SCS are in crystalline state. Similarly, X-ray powder diffraction analysis revealed highly crystalline existence of pure drug, crystalline carriers and developed SCS. The FTIR chemical imaging analysis of SCS formulations showed a homogeneous drug distribution within respective crystalline carriers while an advanced chemical analysis via atomic force microscopy and Raman analysis complemented the foregoing findings. The developed SCS1 formulation showed up to 81 fold increase in the solubility and 4.1 fold increase in the dissolution rate of the drug compared to that of the bulk substance. Surprisingly, the developed SCS formulation remained stable for a period of more than one year at accelerated conditions inferred from dissolution studies. It can be concluded that the SCS approach can be used as an alternative contemporary technique to enhance the dissolution rates of many other poorly water-soluble drugs by means of thermal HME processing.

Design and Evaluation of Topical Diclofenac Sodium Gel Using Hot Melt Extrusion Technology as a Continuous Manufacturing Process with Kolliphor® P407.

The aim of the present context was to develop and evaluate a Kolliphor® P407-based transdermal gel formulation of diclofenac sodium by hot melt extrusion (HME) technology; central composite design was used to optimize the formulation process. In this study, we have explored first time ever HME as an industrially feasible and continuous manufacturing technology for the manufacturing of gel formulation using Kolliphor® P407 and Kollisolv® PEG400 as a gel base. Diclofenac sodium was used as a model drug. The HME parameters such as feeding rate, screw speed, and barrel temperature were crucial for the semisolid product development, and were optimized after preliminary trials. For the processing of the gel formulation by HME, a modified screw design was used to obtain a uniform product. The obtained product was evaluated for physicochemical characterization such as differential scanning calorimetry (DSC), X-ray diffraction (XRD), pH measurement, rheology, surface tension, and texture profile analysis. Moreover, it was analyzed for general appearance, spreadibility, surface morphology, and drug content. The optimized gel formulation showed homogeneity and transparent film when applied on a glass slide under microscope, pH was 7.02 and uniform drug content of 100.04 ± 2.74 (SD = 3). The DSC and XRD analysis of the HME gel formulation showed complete melting of crystalline API into an amorphous form. The Kolliphor® P407 and Kollisolv® PEG400 formed excellent gel formulation using HME with consistent viscoelastic properties of the product. An improved drug release was found for the HME gel, which showed a 100% drug release than that of a marketed product which showed only 88% of drug release at the end of 12 h. The Flux value of the HME gel was 106 than that of a marketed formulation, which showed only about 60 value, inferring a significant difference (P < 0.05) at the end of 1 h. This study demonstrates a novel application of the hot melt extrusion process for manufacturing of topical semisolid products.

Biodegradable Porous Starch Spheres as a Novel Carrier for Enhancement of Dissolution Rate and Oral Bioavailability of Itraconazole.

BACKGROUND: A biodegradable porous starch (BPS) was developed in order to improve dissolution and oral bioavailability of Itraconazole as a poorly water-soluble antifungal drug. METHOD: BPS was developed by converting native starch from hydrogel to alcogel by solvent exchange method. The developed BPS carrier was characterized by SEM and nitrogen adsorption/desorption analysis to understand surface morphology and porosity distribution respectively. Itraconazole (ITR) was loaded on BPS by adsorption mediated solvent evaporation method, which provides a hydrophilic matrix powder. This causes drug distribution within hydrophilic matrix of porous starch. RESULTS: Solid-state characterization of optimized batch (ITR/BPS-3) was performed using DSC, PXRD, FTIR, SEM and FTIR chemical imaging. In vitro dissolution and in vivo pharmacokinetic studies were performed to evaluate therapeutic potential of ITR/BPS-3 system. In vitro studies of ITR: BPS-3 system revealed a burst effect in drug release (93%) compared to marketed product, which showed 90% drug release at the end of 60 min compared to 84% of marketed. Moreover, ITR/BPS-3 system showed improved oral bioavailability up to 3.93 fold and marketed product shows 3.12 fold compared to ITR. CONCLUSION: This effect is due to high surface area, improved wettability and reduced crystallinity of ITR due to its adsorption into BPS. A successful methodology was reported to prepare BPS from raw starch.

Solubility and dissolution enhancement of efavirenz hot melt extruded amorphous solid dispersions using combination of polymeric blends: A QbD approach.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor and categorized in to BCS class II drug. The aim of the present investigation was to apply quality by design approach to enhance the solubility, dissolution and stability of amorphous solid dispersions (ASDs) of efavirenz using a combination of Soluplus® and HPMCAS-HF polymers. In design of experiments, the user defined quadratic model was used to study the effect of variable concentrations of Soluplus® and HPMCAS-HF for the formation of ASDs of efavirenz. Similarly, a prototype ASD was made using Soluplus® as a carrier with efavirenz loading of 30%. The efavirenz ASDs granular extrudates were evaluated for saturation solubility as well as dissolution rate studies. X-ray powder diffraction, Differential scanning calorimetry, Fourier transform infrared, Atomic force microscopy and FTIR imaging to determine the solid state of efavirenz in the ASDs. DSC and XRD data confirmed that bulk crystalline efavirenz transformed to the amorphous form during the hot melt extrusion processing. Prototype ASD batch showed instability upon storage as per ICH guidelines over a period of 6months, observations inferred from DSC, XRD and in vitro dissolution studies. The maximum dissolution rate was observed when Soluplus® and HPMCAS-HF was in ratio of (60:20) as optimized by design of experiments study. Moreover, the optimized ASDs batch were stable at 40°C, 75% RH for a period of 6months without any dissolution rate changes, and remained into amorphous state.

Crosslinked Porous Starch Particles--a Promising Carrier.

UNLABELLED: Background. Starch is one of the most potential natural polymers used for various bio applications. Literature reports a num- ber of modification strategies such as physical, chemical, enzymatic and genetic to enhance the positive attributes and iron out the undesired features of neat starch. OBJECTIVES: To synthesize a crosslinked porous starch (CPS) as an efficient cargo for the delivery of calcium carbonate in an efficiently controlled manner for the treatment of hyperphosphatemia. MATERIAL AND METHODS: The CPS carrier was synthesized using a natural crosslinker, malic acid. The drug delivery system was formulated, followed by the in situ loading of calcium carbonate during the preparation of the CPS. The developed system was characterized with respect to FTIR, DSC, SEM, moisture content, zeta potential, encapsulation efficiency, phosphate binding efficiency and dissolution studies. RESULTS: The developed formulation was observed to deliver calcium carbonate in an enterically controlled manner. The binding of calcium to phosphate was established to be pH dependent and efficient at pH 7. The moisture content of CPS was in the range of 0.2-0.8%. The zeta potential of the colloidal system was noted to be sufficiently high, indicating the stability. The encapsulation efficiency of CPS particles for calcium was found to be 88-96%. CONCLUSIONS: An efficient, cost-effective, facile and commercially-viable formulation was demonstrated to deliver calcium carbonate for the treatment of hyperphosphatemia.

Modified extrusion-spheronization as a technique of microencapsulation for stabilization of choline bitartrate using hydrogenated soya bean oil.

INTRODUCTION: Choline bitartrate (CBT) is a vital nutrient for fetal brain development and memory function. It is hygroscopic in nature which is associated with stability related problem during storage such as development of fishy odor and discoloration. AIM: Microencapsulation method was adopted to resolve the stability problem and for this hydrogenated soya bean oil (HSO) was used as encapsulating agent. MATERIALS AND METHODS: Industrially feasible modified extrusion-spheronization technique was selected for microencapsulation. HSO was used as encapsulating agent, hydroxypropyl methyl cellulose E5/E15 as binder and microcrystalline cellulose as spheronization aid. Formulated pellets were evaluated for parameters such as flow property, morphological characteristics, hardness-friability index (HFI), drug content, encapsulation efficiency, and in vitro drug release. The optimized formulations were also characterized for particle size (by laser diffractometry), differential scanning calorimetry, powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy, and scanning electron microscopy. RESULTS AND DISCUSSIONS: The results from the study showed that coating of 90% and 60% CBT was successful with respect to all desired evaluation parameters. Optimized formulation was kept for 6 months stability study as per ICH guidelines, and there was no change in color, moisture content, drug content, and no fishy odor was observed. CONCLUSION: Microencapsulated pellets of CBT using HSO as encapsulating agent were developed using modified extrusion spheronization technique. Optimized formulations, CBT 90% (F5), and CBT 60% (F10), were found to be stable for 4M and 6M, respectively, at accelerated conditions.