Angus H. Forster

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.

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.

Melt Extrusion and Spray Drying of Carbamazepine and Dipyridamole with Polyvinylpyrrolidone/Vinyl Acetate Copolymers

Aim: Carbamazepine and dipyridamole are class II compounds (BCS) whose oral bioavailability is limited by poor solubility. The use of glass solutions to improve the bioavailability of this class of compound has been an area of research for a number of years. The influence of polymer parameters (Tg, hydrophilicity, solubility parameter, and ability to hydrogen bond) on glass solution properties is investigated. Methods: Carbamazepine and dipyridamole glass solutions are prepared with PVP/VA 64 and PVP/VA 37 by spray drying and melt extrusion. The products are then characterized by XRPD, thermal, and spectroscopic methods. Yield, physical stability, and dissolution profiles are also assessed. Results: The properties of the polymer greatly influenced the ability to produce glass solutions. With decreases in Tg and hydrophilicity, melt extrusion became the more viable of the two preparative techniques. Although glass solutions were successfully prepared, the greater the difference in component solubility parameter, the less physically stable the formulation. Conclusion: Consideration must be given to the characteristics of the polymer when selecting for glass solution formulation. Although a number of process parameters can be varied for melt extrusion and spray drying, their ability to overcome fundamental differences in the physical parameters discussed is limited.