John Hempenstall

Characterization of glass solutions of poorly water-soluble drugs produced by melt extrusion with hydrophilic amorphous polymers

Indomethacin, lacidipine, nifedipine and tolbutamide are poorly soluble in water and may show dissolution‐related low oral bioavailability. This study describes the formulation and characterization of these drugs as glass solutions with the amorphous polymers polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone‐co‐vinyl acetate by melt extrusion. The extrudates were compared with physical mixtures of drug and polymer. X‐ray powder diffraction, thermal analysis, infrared spectroscopy, scanning electron microscopy, HPLC, moisture analysis and dissolution were used to examine the physicochemical properties and chemical stability of the glass solutions prepared by melt extrusion at a 1:1 drug/polymer ratio. Depending on the temperature used, melt extrusion produced amorphous glass solutions, with markedly improved dissolution rates compared with crystalline drug. A significant physicochemical interaction between drug and polymer was found for all extrudates. This interaction was caused by hydrogen bonding (H‐bonding) between the carbonyl group of the pyrrole ring of the polymer and a H‐donor group of the drug. Indomethacin also showed evidence of H‐bonding when physical mixtures of amorphous drug and PVP were prepared. After storage of the extrudates for 4–8 weeks at 25°C/75% relative humidity (RH) only indomethacin/polymer (1:1) extrudate remained totally amorphous. All extrudates remained amorphous when stored at 25°C/< 10% RH. Differences in the physical stability of drug/polymer extrudates may be due to differences in H‐bonding between the components.

Media to simulate the postprandial stomach I. Matching the physicochemical characteristics of standard breakfasts.

To better predict food effects on the bioavailability/bioequivalence of drugs and drug products from in‐vitro data, a dissolution medium that simulates the initial composition of the postprandial stomach was developed. First, the physical parameters of two homogenized standard breakfasts often administered to assess food effects in pharmacokinetic studies were measured. These included pH, buffer capacity, osmolality, surface tension and viscosity. Subsequently, the match of the physical parameters of several commercially available liquid meals, including long‐life milk, Ensure and Ensure Plus to those of the breakfasts was evaluated. Of the three liquid meals studied, Ensure Plus had the closest physicochemical behaviour to that of homogenized standard breakfasts. By increasing the viscosity of Ensure Plus with 0.45% pectin, it was possible to obtain a medium that closely resembles the FDA standard breakfast.

The potential of small-scale fusion experiments and the Gordon-Taylor equation to predict the suitability of drug/polymer blends for melt extrusion

The aim of this study was to investigate the use of small-scale fusion experiments and the Gordon-Taylor (GT) equation to predict whether melt extrusion of a drug with an amorphous polymer produces a stable amorphous dispersion with increased drug dissolution. Indomethacin, lacidipine, nifedipine, piroxicam, and tolbutamide were used as poorly soluble drugs. Drug/polyvinylpyrrolidone (PVP) blends were prepared at a 1:1 mass ratio. Small-scale fusion experiments were performed in a differential scanning calorimeter (DSC) and in stainless steel beakers. Extrusion was performed in a Brabender Plasti-corder. The glass transition temperatures Tg were determined by DSC. Taking an average Tg from the DSC melt, beaker melt, and GT equation accurately predicted the extrudate Tg. Physical stability of beaker melt and extrudate samples was tested by X-ray powder diffraction (XRPD) and DSC after storage at 30°C (beaker melt) or 25°C (extrudate) and less than 10%, 60%, and 75% relative humidity (RH). Beaker melts were amorphous, apart from some residual crystallinity. Extrudates were amorphous after preparation. Except for indomethacin/PVP, which remained amorphous, the crystallinity of beaker melts and extrudates increased only at 75% RH. Recrystallization occurred even when the Tg of the sample was well above the storage temperature. Chemical stability of the beaker melts and extrudates was tested by capillary electrophoresis and high-performance liquid chromatography (HPLC). Stability was slightly improved in the extrudate compared to the beaker melt. In general, the order for rate of dissolution was crystalline drug was less than the physical mixture, which was less than the drug/PVP beaker melt, which was approximately equal to the extrudate. The use of beaker melts allows a conservative estimate of the potential to melt extrude a drug. To predict physical stability, analysis of the Tg must be combined with physical stability experiments.

A comparative study of different release apparatus in generating in vitro–in vivo correlations for extended release formulations

The importance of hydrodynamics in the development of in vitro-in vivo correlations (IVIVCs) for a BCS Class II compound housed in a hydrophilic matrix formulation and for a BCS Class I compound housed in an osmotic pump formulation was assessed. In vitro release data were collected in media simulating the fasted state conditions in the stomach, small intestine and the ascending colon using the USP II, the USP III and the USP IV release apparatuses. Using the data collected with the USP II apparatus, the plasma profiles were simulated and compared with human plasma profiles obtained after administration of the same dosage forms to healthy fasted volunteers. Data obtained with the USP III and USP IV apparatuses were directly correlated with the deconvoluted human plasma profiles. In vitro hydrodynamics affected the release profile from the hydrophilic matrix. For both formulations, based on the values of the difference factor, all three apparatuses were equally useful in predicting the actual in vivo profile on an average basis. Although some hydrodynamic variability is likely with low solubility drugs in hydrophilic matrices, the hydrodynamics of USP II, III and IV may all be adequate as a starting point for generating IVIVCs for monolithic dosage forms in the fasted state.

Factors affecting incorporation of drug into solid solution with HPMCP during solvent change co-precipitation.

Drug-hydroxypropyl methylcellulose phthalate (HPMCP) mixtures were completely dissolved in acetone, and the resulting solution was added drop-wise into HCl(aq). Resulting co-precipitates were filtered, and then dried under vacuum at 45 degrees C, -800 mbar for 24 h. Modulated differential scanning calorimetry, thermogravimetric analysis, X-ray powder diffraction and HPLC were used to detect and quantify different phases present in co-precipitates. A 1/8 factorial study followed by a circumscribed central composite (CCC) study of significant factors, were used to detect and quantify respectively, the effects that processing factors had on the percentage of drug present in co-precipitates which was incorporated into solid solution (the response). Robustness of the model obtained from the CCC study was tested. Statistically significant factors were found to be the percentage of drug added into solvent, stirrer speed, and antisolvent pH. The statistically significant mathematical model obtained from the CCC study predicted that the dominant factor influencing the response is the percentage of drug added into solvent. The effect of stirrer speed on the response includes a local maximum at stirrer speed approximately 700 rpm. Both stirrer speed and antisolvent pH showed interactions with the percentage of drug added into solvent. The model obtained from this study indicated the possibility of two opposing phenomena influencing the response: crystallization inhibition by HPMCP, and solvent-antisolvent plasticization. Testing of this model using eight experimentally determined points showed reasonable robustness, with six out of eight points lying inside 95% prediction intervals.

Solvent change co-precipitation with hydroxypropyl methylcellulose phthalate to improve dissolution characteristics of a poorly water-soluble drug.

Research compound GWX belongs to biopharmaceutical classification system type II, and hence shows dissolution‐rate‐limited absorption. To improve its dissolution performance, GWX was formulated as a co‐precipitate with hydroxypropyl methylcellulose phthalate (HPMCP). Co‐precipitates with various drug‐HPMCP ratios were prepared and characterised using modulated differential scanning calorimetry (MDSC), X‐ray powder diffraction, HPLC and dissolution testing. Co‐precipitates with 1: 9 and2: 8 drug‐HPMCP ratios showed the highest extent of dissolution after both 5 and 90 min, followed by 3: 7, 4: 6, and 5: 5 drug‐HPMCP co‐precipitates, in respective order. Co‐precipitates with drug‐HPMCP ratios of 6: 4 and greater showed no significant improvement in dissolution over crystalline drug alone. The amounts of crystalline and amorphous drug in co‐precipitates, as determined by MDSC, and HPLC quantification of the total amount of drug in co‐precipitates were used to determine the amount of drug incorporated into solid solution. It was found that dissolution rate and extent was correlated to the amount of drug incorporated into amorphous solid solution for the 1:9 to 5: 5 drug‐HPMCP ratio co‐precipitates. Amorphous drug alone and physical mixtures of drug and HPMCP showed very little and no significant improvement in dissolution rate or extent, respectively, above crystalline drug alone. Amorphous drug alone re‐crystallized to a large extent within 1 min of contact with the dissolution medium, whereas 4: 6 drug‐HPMCP co‐precipitate showed a lower degree of re‐crystallization and 2: 8 drug‐HPMCP co‐precipitate showed very little re‐crystallization. It was concluded that the likely mechanisms of improved dissolution of low drug‐HPMCP ratio co‐precipitates were improved wetting or increased surface area for mass transfer, thermodynamically enhanced dissolution of a higher energy amorphous form and inhibition of re‐crystallization, when drug was incorporated into solid solution.

Physical stability and enthalpy relaxation of drug‐hydroxypropyl methylcellulose phthalate solvent change co‐precipitates

The poorly water‐soluble drug GWX was co‐precipitated with hydroxypropyl methylcellulose phthalate (HPMCP) using a solvent change method. The two co‐precipitate formulations made, with drug‐HPMCP ratios of 2:8 and 5:5, were analysed using modulated temperature differential scanning calorimetry. They were found to consist of completely amorphous solid solution and a mixture of amorphous solid solution, crystalline drug and amorphous drug, respectively. Stability with respect to crystallization of the two co‐precipitates and pure amorphous drug made by quench cooling was compared by storing preparations at 25°C and 40°C, under vacuum over P2O5, and at 75% relative humidity (r.h.). Humidity (75% r.h. compared with dry) had a larger influence on crystallization of the amorphous drug than temperature (25°C compared with 40°C). The solid solution phase in co‐precipitates had a relatively higher stability than amorphous drug alone, with respect to crystallization, in presence of the plasticizer water, and crystalline drug. These findings were partly explained by evidence of decreased molecular mobility in the amorphous solid solution with respect to amorphous drug alone, using enthalpy relaxation measurements. At an ageing temperature of 65°C, the calculated half‐life for enthalpy relaxation of the 2:8 drug–HPMCP ratio coprecipitate was about 6 orders of magnitude greater than that of amorphous drug alone, indicating a large difference in relative molecular mobility.