(M1530-07-39) Compression-Induced Destabilization in Chlorpropamide-PVPVA Amorphous Solid Dispersions

Purpose: Formation of an amorphous solid dispersion (ASD) by forming a drug-in-polymer composite with a high glass-transition temperature (T_g) can inhibit recrystallization of the active pharmaceutical ingredient (API), while increasing its apparent solubility and oral bioavailability. Physical destabilization can occur when processing ASDs after their formation causes recrystallization. Pressure applied during tablet compaction can initiate a solid-state transformation of the amorphous API, depending on the ASD composition and the applied force. The aim of the present work was to investigate compression-induced destabilization of chlorpropamide-PVPVA ASDs by monitoring the timeframe for appearance of crystallinity in milled ASDs and compacts.

Methods: ASDs containing chlorpropamide were prepared with PVPVA by melt-quenching at 75% w/w drug-loading. Glasses were converted to a powder by cryomilling at 10 Hz in alternating 2 min milling and sample cool-down periods. All samples were stored in a P<sub>2O₅ desiccator and equilibrated to ambient temperature before opening, to minimize water condensation. Both melt-quenched ASDs and cryomilled samples were characterized 24 h after preparation using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and polarized light microscopy (PLM). The cryomilled ASD powders were compacted using an Instron 5869 Universal Material Testing System (Norwood, MA) fitted with a 50 kN load cell. For each compact, 200 mg of powder was loaded into a 10 mm cylindrical die and compressed at forces of 5, 10, and 30 kN. For comparison, a ternary component compact was prepared by adding 10% microcrystalline cellulose MCC) to the cryomilled ASD, which was compressed at 10 kN. Recrystallization in compacts was monitored by collecting PXRD patterns using an Empyrean third generation system (PANalytical B.V., Almelo, the Netherlands). Samples were irradiated with CuKα X-rays (λ = 1.5406 Å), generated at 45 kV and 40 mA. Data were collected from 5–60° 2θ at an angular step of 0.0080° 2θ; irradiation time was 50.16 s/step.

Results: Neither the melt-quenched ASDs nor the cryomilled samples showed birefringence in photomicrographs taken during PLM characterization after 24 h (Figure 1). The DSC thermograms (Figure 2) also showed that both sample types were initially amorphous, having a single T_g ~22°C, while the respective PXRD patterns showed no characteristic diffraction attributable to the API (Figure 3). PXRD patterns collected immediately following preparationof the chlorpropamide-PVPVA ASDs compacted at 30 kN, revealed two characteristic chlorpropamide peaks at 6.6° and 18.2° 2θ, suggesting that detectable crystallization was induced during compaction (Figure 3). In contrast, neither the 5 kN nor 10 kN compacts showed diffraction peaks attributable to chlorpropamide, when characterized after consolidation. Periodic PXRD was used to monitor crystallization in ASDs and compacts for 14 weeks. Diffraction attributable to chlorpropamide was observed after 5 weeks of storage for both the 5 and 10 kN binary compacts, but not until 8 weeks storage for the cryomilled ASDs. Diffraction patterns for the ternary compacts (containing MCC), did not show evidence of chlorpropamide crystallization for 14 weeks following compression.

Conclusion: Characterization of the melt-quenched ASDs and cryomilled samples revealed that the chlorpropamide remained amorphous through preparation, without immediate crystallization induced during cryomilling; diffraction attributable to chlorpropamide was not observed for 8 weeks. Subsequent compaction at 30 kN induced immediate crystallization of the API, suggesting that the force and consequent internal temperature may have played a role in destabilization. Immediate PXRD characterization of the 5 and 10 kN compacts showed no detectable diffraction from the API, likely meaning that the extent of chlorpropamide recrystallization was less than the limit of detection for this technique. Emergence of characteristic diffraction peaks in the 5 and 10 kN compacts after 5 weeks of storage suggests that compaction using lower forces induced seed crystals of chlorpropamide, which then led to recrystallization over time. In ternary compacts, prepared at 10 kN, the MCC helped resist destabilization for up to 14 weeks after preparation, suggesting that this additional component may have provided a physical barrier against solid-state diffusion of the API in situ.

Figure 1: PLM data of chlorpropamide-PVPVA melt-quenched ASD (A) and Cryomilled ASD (B) showing that the samples were amorphous.

Figure 2: DSC thermogram of chlorpropamide-PVPVA melt-quenched ASD (red) and Cryomilled ASD (pink) confirming formation of amorphous dispersions with a single Tg ~22°C.

Figure 3: PXRD patterns of chlorpropamide-PVPVA Cryomilled and melt-quenched ASD, binary and ternary compacts of chlorpropamide-PVPVA ASD compressed at different compression force, Chlorpropamide API and reference pattern.