Optimizing Nonsink Dissolution Testing for Amorphous Solid Dispersions: Exploring Sample Handling Variables.

This study aims to investigate key variables affecting the dissolution of amorphous pharmaceuticals. We examined sample treatment methods (centrifugation vs syringe filtration), time delays between sample collection and processing (immediate, 2, or 24 h), and different sample preparations (bare powder, capsules, or tablets). These factors were evaluated through both sink and nonsink dissolution experiments, using controlled supersaturation conditions (sink index ≈ 0.1) with amorphous solid dispersions (ASDs) containing low-substituted hydroxypropyl cellulose (L-HPC) and either indomethacin or posaconazole as model drugs. Our results highlighted the significant impact of syringe filtration on nonsink dissolutions, particularly the notable reduction in dissolved drug concentration, possibly due to filtration-induced precipitation. Moreover, introducing a delay of 2 or 24 h between sample collection and quantitation under nonsink conditions led to substantial concentration changes. This effect was not as pronounced when samples underwent centrifugation, and only the analysis was delayed for 2 h. The findings also emphasize the importance of accounting for delays introduced by pharmaceutical formulations, particularly in assessing the kinetic-solubility profiles of ASDs. This research offers valuable insights into the field of ASDs, enhancing our understanding of how these variables can influence dissolution results.

Amorphous solid dispersions in high-swelling, low-substituted hydroxypropyl cellulose for enhancing the delivery of poorly soluble drugs.

Amorphous solid dispersions (ASDs) based on water-insoluble hydrophilic polymers can sustain supersaturation in their kinetic solubility profiles (KSPs) compared to soluble carriers. However, in the limit of very high swelling capacity, the achievable extent of drug supersaturation has not been fully examined. This study explores the limiting supersaturation behavior of ASDs of poorly soluble indomethacin (IND) and posaconazole (PCZ) based on a high-swelling excipient, low-substituted hydroxypropyl cellulose (L-HPC). Using IND as a reference, we showed that the rapid initial supersaturation buildup in the KSP of IND ASD can be simulated through sequential IND infusion steps, however at large times the KSP of IND release from ASD appears more sustained than direct IND infusion. This has been attributed to potential trapping of seed crystals generated in the L-HPC gel matrix thus limiting their growth and rate of desupersaturation. Similar result is also expected in PCZ ASD. Furthermore, the current drug loading process for ASD preparation resulted in the agglomeration of L-HPC based ASD particles, producing granules of up to 300-500 µm (cf. 20 µm individual particle), with distinct kinetic solubility profiles. This feature makes L-HPC particularly suitable as ASD carriers for fine tuning of supersaturation to achieve enhanced bioavailability for poorly soluble drugs.

Combining amorphous solid dispersions for improved kinetic solubility of posaconazole simultaneously released from soluble PVP/VA64 and an insoluble ammonio methacrylate copolymer.

The aim of this study was to evaluate the potential of combining multiple ASDs based on water soluble and insoluble polymers to reach and maintain poorly soluble posaconazole (PCZ) supersaturation over time. ASDs of PCZ were obtained with PVP/VA64 or an ammonio methacrylate copolymer by solvent evaporation method with a fixed 20% (wt/wt%) drug loading ratio and physical mixtures of these ASDs were prepared at various proportions. ASDs were characterized by Fourier transform infrared spectroscopy (FT-IR) and powder X-ray diffraction (PXRD) and compared to their respective physical mixture with crystalline PCZ. Crystalline PCZ equilibrium solubility was determined at pH 1.2-2 range. Dissolution profiles were constructed under non-sink condition with an adapted dissolution system. PXRD analysis demonstrated that both ASDs were at the amorphous state and FT-IR spectroscopy revealed that the analytical signal of PCZ was also absent in both ASDs. Equilibrium solubility of crystalline PCZ varied between 26.36 ±â€¯0.32 (pH 2) to 609.33 ±â€¯3.68 (pH 1.2) µg/mL. All ASDs reached higher concentrations than the equilibrium solubility of crystalline PCZ during dissolution. PVP/VA64 ASDs showed dominance over PCZ dissolution and recrystallization rates whereas Eudragit RS PO ASD alone did not cause PCZ recrystallization whatsoever. The combination containing 20 mg PVP/VA64 + 80 mg Eudragit RS PO as PCZ carriers obtained the highest AUC, suggesting that even after the PVP/VA64 part was completely dissolved, reaching a concentration above crystalline PC Cs, the insoluble polymer could still release PCZ slowly and maintain supersaturation over time. The research demonstrated a potential of combining multiple ASDs to achieve distinct dissolution profiles while increasing the kinetic solubility of poorly soluble drugs.

Simultaneous Quantification of Benznidazole and Posaconazole by HPLC-DAD Using QbD Approach.

OBJECTIVE: To develop an analytical method to simultaneous quantification of benznidazole (BNZ) and posaconazole (POS) by high-performance liquid chromatography with diode-array detection (HPLC-DAD) using design of experiments. METHODS: Percentages of organic phase, buffer pH and flow rates of mobile phase were selected as independent variables by full factorial design (33), totaling 27 experiments. Significant factors were evaluated using factorial analysis of variance with 95% confidence level. Method optimization was performed using desirability profiles, considering BNZ/POS chromatographic resolution and peak areas. Further, the method was evaluated regarding its suitability and properly validated according to the international compendiums using the parameters: specificity, linearity, accuracy, precision, limit of detection and limit of quantification. RESULTS: The optimized method was achieved using Discovery® C8 column (250 mm × 4.6 mm; 5 µm particle size), methanol/acetate buffer (pH 3.5)(71:29) and detection at 260 nm. Retention times were 3.6 and 7.6 min for BNZ and POS, respectively, with good suitability of system and it was specific and linear (r2 >0.99) for both drugs, proving the efficiency of the method even in the presence of degradation products of POS. CONCLUSION: This new method is a great alternative to perform reliable, faster and cheaper analysis since the simultaneous quantification of the association BZN/POS is not reported yet in the literature.