Influence of Plasdone™ S630 Ultra-an Improved Copovidone on the Processability and Oxidative Degradation of Quetiapine Fumarate Amorphous Solid Dispersions Prepared via Hot-Melt Extrusion Technique.

In a formulation, traces of peroxides in copovidone can impact the stability of drug substances that are prone to oxidation. The present study aimed to investigate the impact of peroxides in novel Plasdone™ S630 Ultra and compare it with regular Plasdone™ S630 on the oxidative degradation of quetiapine fumarate amorphous solid dispersions prepared via hot-melt extrusion technique. The miscibility of copovidones with drug was determined using the Hansen solubility parameter, and the results indicated a miscible drug-polymer system. Melt viscosity as a function of temperature was determined for the drug-polymer physical mixture to identify the suitable hot-melt extrusion processing temperature. The binary drug and polymer (30:70 weight ratio) amorphous solid dispersions were prepared at a processing temperature of 160°C. Differential scanning calorimetry and Fourier transform infrared spectroscopy studies of amorphous solid dispersions revealed the formation of a single-phase amorphous system with intermolecular hydrogen bonding between the drug and polymer. The milled extrudates were compressed into tablets by using extragranular components and evaluated for tabletability. Stability studies of the milled extrudates and tablet formulations were performed to monitor the oxidative degradation impurity (N-oxide). The N-oxide impurity levels in the quetiapine fumarate - Plasdone™ S630 Ultra milled extrudates and tablet formulations were reduced by 2- and 3-folds, respectively, compared to those in quetiapine fumarate - Plasdone™ S630. The reduced oxidative degradation and improved hot-melt extrusion processability of Plasdone™ S630 Ultra make it a better choice for oxidation-labile drugs over Plasdone™ S630 copovidone.

The Effect of Process Variables and Binder Concentration on Tabletability of Metformin Hydrochloride and Acetaminophen Granules Produced by Twin Screw Melt Granulation with Different Polymeric Binders.

In twin screw melt granulation, granules are produced by passing mixtures of drug substances and polymeric binders through twin screw extruder such that temperatures are maintained below melting point of drugs but above glass transition of polymers used, whereby the polymers coat surfaces of drug particles and cause their agglomeration into granules. Since various formulation factors, such as binder type and concentration, and processing variables like extrusion temperature, screw configuration, and screw speed, can influence the granulation process, the present investigation was undertaken to study their effects on tabletability of granules produced. Three different types of polymeric binders, Klucel® EXF (hydroxypropyl cellulose), Eudragit® EPO (polyacrylate binder), and Soluplus® (polyvinyl caprolactam-co-vinyl acetate-ethylene glycol graft polymer), were used at 2, 5, and 10% concentrations. Metformin hydrochloride (HCl) (mp: 222°C) and acetaminophen (mp: 169°C) were used as model drugs, and drug-polymer mixtures with metformin HCl were extruded at 180, 160, and 130°C, while those with acetaminophen were extruded at 130 and 110°C. Other process variables included screw configurations: low, medium, and high shear for metformin HCl, and low and medium shear for acetaminophen; feed rates: 20 and 60 g/min; and screw speed of 100 and 300 RPM. Formulation and process variables had significant impact on tabletability. The target tensile strength of ≥2 MPa could be obtained with all polymers and at all processing temperatures when metformin HCl was granulated at 180°C and acetaminophen at 130°C. At other temperatures, the target tensile strength could be achieved at certain specific sets of processing conditions.

Stable amorphous solid dispersions of fenofibrate using hot melt extrusion technology: Effect of formulation and process parameters for a low glass transition temperature drug.

Development of stable amorphous solid dispersions (ASDs) for a low glass transition temperature (Tg) drug is a challenging task. The physico-chemical properties of the drug and excipients play a critical role in developing stable ASDs. In this study, ASDs of poorly soluble fenofibrate, a drug with a low Tg, were formulated using hydroxy propyl methylcellulose acetate succinate (HPMCAS) via hot melt extrusion (HME). The feasible processing conditions were established at varying drug loads and processing temperatures. The prepared ASDs were characterized for crystallinity using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Fourier transform-infrared spectroscopy was performed to study the potential interactions. DSC and PXRD studies confirmed the amorphous state of fenofibrate in the prepared ASDs. A discriminative in vitro dissolution method was established to study the impact of HPMCAS grades on dissolution profile. The dissolution parameters such as dissolution efficiency, initial dissolution rate and mean dissolution rate, suggested improved dissolution characteristics compared to pure fenofibrate. Accelerated stability studies at 40 °C/75% RH showed preservation of the amorphous nature of fenofibrate in formulations with 15% drug load and in vitro drug release studies indicated similar release profiles (f2 >50). This study provides an insight into the formulation and processing of ASDs for poorly soluble drugs with low Tg.

Conversion of α-lactose monohydrate to anhydrous form with superior tabletability by twin-screw extrusion at elevated temperature.

The purpose of this study was to improve tabletability (tensile strength versus compaction pressure) of α-lactose monohydrate by twin screw extrusion (TSE) near its dehydration temperature but below its melting point. When extruded at 150 and 160 °C, α-lactose monohydrate converted completely to α-lactose anhydrous that was mostly crystalline and only partially amorphous; the latter was indicated by glass transition observed in DSC scans. Tabletability of the material thus obtained by TSE was superior to anhydrous lactose available commercially or produced by hot air oven drying at 160 °C. The superior tabletability was attributed to the partial conversion to amorphous lactose. When samples of anhydrous lactose powders obtained by TSE or oven drying were exposed to 25 °C/60% RH and 40 °C/75% RH, they reverted to the monohydrate with decreased tabletability. However, when anhydrous lactose powders produced by TSE were first compressed into tablets with high tensile strength and then exposed to similar stability testing conditions, there was no decrease in the tensile strength of tablets. Rather, it further increased, possibly due to the interaction of the amorphous fraction of lactose with moisture. Thus, TSE not only increased tabletability of α-lactose monohydrate, the compressed tablets remained intact and hard during shelf-life. These results demonstrate that a new modified anhydrous lactose may be produced by TSE that has better tabletability and superior physical stability than α-lactose monohydrate and the commercially available anhydrous lactose.

Hypromellose acetate succinate based amorphous solid dispersions via hot melt extrusion: Effect of drug physicochemical properties.

In this study, the impact of drug and hydroxypropyl methylcellulose acetate succinate (HPMCAS) grades physicochemical properties on extrusion process, dissolution and stability of the hot melt extruded amorphous solid dispersions (ASDs) of nifedipine and efavirenz was investigated. Incorporation of drugs affected the extrusion temperature required for solid dispersion preparation. Differential scanning calorimetry and powder X-ray diffraction studies confirmed the amorphous conversion of the drugs in the prepared formulations. The amorphous nature of ASDs was unchanged after 3 months of stability testing at 40 °C and 75% relative humidity. The dissolution efficiency of the ASDs was dependent on the log P of the drug. The inhibitory effect of HPMCAS on drug precipitation was dependent on the hydrophobic interactions between drug and polymer, polymer grade, and dose of the drug. The dissolution efficiency and dissolution rate of the ASDs were dependent on the log P of the drug and solubility and hydrophilicity of the polymer grade respectively. The inhibitory effect of HPMCAS on drug precipitation was dependent on the hydrophobic interactions between drug and polymer, polymer grade, and the dissolution dose of the drug.

Processability of AquaSolve™ LG polymer by hot-melt extrusion: Effects of pressurized CO2 on physicomechanical properties and API stability.

The objective of this study was to investigate the processability of AquaSolve™ hydroxypropyl methylcellulose acetate succinate L grade (HPMCAS LG) via hot-melt extrusion and to examine the effect of pressurized carbon dioxide (P-CO2) on the physicomechanical properties of efavirenz (EFA)-loaded extrudates. To optimize the process parameters and formulations, various physical mixtures of EFA (30%, 40%, and 50%, w/w) and HPMCAS LG (70%, 60%, and 50%, w/w), respectively, were extruded using a co-rotating twin-screw extruder with a standard screw configuration, with P-CO2 injected into zone 8 of the extruder. Thermal characterization of the extrudates was performed using differential scanning calorimetry and thermogravimetric analysis. Scanning electron microscopy was employed to study the morphology and porosity of the formulations. Notably, the macroscopic morphology changed to a foam-like structure by P-CO2 injection resulting in an increased specific surface area, porosity, and dissolution rate. Thus, HPMCAS LG extrusion, coupled with P-CO2 injection, yielded faster dissolving extrudates. Stability studies indicated that HPMCAS LG was able to physically and chemically stabilize the amorphous state of high-dose EFA. Furthermore, the milling efficiency of the extrudates produced with P-CO2 injection improved because of their increased porosity.

Investigating the Use of Polymeric Binders in Twin Screw Melt Granulation Process for Improving Compactibility of Drugs.

Traditionally, the melt granulation for pharmaceutical products was performed at low temperature (<90°C) with high-shear granulators using low-melting waxy binders, and tablets produced using such granules were not amenable to large-scale manufacturing. The situation has changed in recent years by the use of twin screw extruder where the processing temperature could be increased to as high as 180°C and polymers with high Tg could be used as binders. In this study, different polymeric binders were screened for their suitability in improving compactibility of 2 drugs, metformin hydrochloride and acetaminophen, by twin screw melt granulation. Processing temperatures for the 2 drugs were set at 180°C and 130°C, respectively. Screw configuration, screw speed, and feed rate were optimized such that all polymeric binders used produced granules. Several hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and methacrylate-based polymers, including Klucel® EXF, Eudragit® EPO, and Soluplus®, demonstrated good tablet tensile strength (>2 MPa) when granules were produced using only 10% wt/wt polymer concentration. Certain polymers provided acceptable compactibility even at 5% wt/wt. Thus, twin screw melt granulation process may be used with different polymers at a wide range of temperature. Due to low excipient concentration, this granulation method is especially suitable for high-dose tablets.