(M1030-11-63) Investigation of Interplay between API Processing Method and Modified Release Matrix Tablet on Dissolution Performance

Purpose: Modified release dosage forms aim to keep the drug’s plasma level in the therapeutic range and reduce the dosing frequency. This study investigates the interplay between a sustained release matrix and the physical properties of a weakly acidic drug. The drug is poorly soluble in gastric fluid, which is expected to result in slower drug release. This is not desirable, as dissolution should be driven by the matrix. The release is optimized by the manufacturing method of the drug product in such a way that the release becomes independent from the intestinal pH and from the pH solubility profile of the drug. One of the strategies to overcome this challenge is the API processing by particle size reduction or solid-state form improvement. By reducing the particle size of an API, the specific surface area is increased thereby dissolving more quickly at a low pH. The different solid-state forms present in the formulated drug product contributed to the modified dissolution profile. The objective of this investigation was to examine the effect of particle size reduction and solid-state form of a poorly water-soluble API at acidic conditions on its dissolution rate from a typical modified release composition in neutral and gastric pH environments: (1) Non-processed API; (2) API particle size reduction via jet micronization; (3) API particle size reduction via wet nanomilling; (4)API dissolved in granulation solvent (ethanol)

Methods: The formulation contains a weakly acidic API (pKa 4, solubility at pH 7.3 is 1.8 mg/mL and at 1.0 is < 0.6 µg/mL), HPMC (Methocel^TM K4M Premium CR, Methocel^TM K100 Premium LVCR), Avicel^® PH102, Pearlitol^® 100 SD, Aerosil^® 200 Pharma and HYQUAL^TM 5712 vegetable. Ethanol 99.2% was used for dissolving the API. Micronization of the API was performed using an air-jet mill (MC DecJet^® 30), with an injection pressure of 6 bar, grinding pressure of 3 bar. The micronized API was further characterized, blended with the excipients, and compressed into tablets. Nanomilling was performed by dual centrifugation. The API (5% w/v) was suspended in an aqueous HPMC solution (1%) and 0.3 mm ZrO milling beads. Samples from the suspensions were drawn after milling for further characterization. The suspension was added in a high-shear mixer with the excipients, dried, and compressed into tablets. The non-processed API was processed to the MR dosage form like the micronized variant. For the ethanolic granulation, the API was dissolved in ethanol, sprayed on the excipients in a high-shear mixer and further processed to tablets. To assess the API’s solid-state form after dissolution in ethanol and drying, the API was dissolved in ethanol and the organic solvent was evaporated at room temperature overnight. The dried material was further characterized. The non-processed, micronized, nanomilled, and solvent casted API were characterized in terms of solid-state properties by laser diffraction particle size analysis, polarized light microscopy, XRD (X-ray diffraction), and DSC (differential scanning calorimetry). In vitro dissolution studies of the tablets were performed at pH 6.8 phosphate buffer and 0.1N HCl at 37°C.

Results: Solid-State Characterization: The particle size, expressed as d(0.5) was 51 µm for the non-processed API, 3.1 µm for the micronized, and 152 nm for the nanomilled API. As shown in Figure 1, API crystallinity is confirmed in all cases by the birefringence observed under polarized microscopy, and this is confirmed by XRD. However, the diffractogram of solvent casted API showed differences in the XRD pattern compared to non-processed API and milled API, indicating the presence of a different polymorph. In addition, the corresponding exothermic peak at around 80°C on the DSC thermogram could be explained by the new polymorph which transforms to the original polymorphic form. The original polymorph melts at 129°C. The new polymorph in combination with crystal size is likely responsible for the faster dissolution rate at pH 1.0. For the milled samples, no change in solid-state form was observed. In vitro dissolution profiles: Tablets were tested for dissolution in 0.1 N HCl and in pH 6.8 media, respectively. The dissolution profiles in pH 6.8 showed no relevant differences for the different processing methods (Figure 2). Dissolution in pH 1.0 was overall slower and the profiles differentiated between the manufacturing methods indicating the drug release was driven by the API solubility, and not as desired by the matrix. A decreased particle size increased dissolution rate (non-processed API < micronized < nanomilled). The highest dissolution rate was achieved for the ethanolic granulation process.

Conclusion: The present study demonstrates the relevance of a comprehensive investigation of the dissolution performance of a matrix tablet over the biorelevant pH range. The difference of dissolution performance at pH 1.0 compared to pH 6.8 was reduced by using different API processing methods. In an acidic environment it was demonstrated that a complex interplay between API processing method and modified release matrix tablet resulted in improved dissolution performance.

Acknowledgements: Conflicts of Interest: Leire Pérez-Ibarbia, Stefanie Avril, Markus von Raumer, Giorgio Marino, Oliver Schinzinger, Alexander Denninger are employees of Corden Pharma. They have no additional conflicts of interest to report.


Figure 1: Solid-state characterization (polarized light microscope, XRD diffractogram, DSC thermogram) of the processed and non-processed API


Figure 2: Dissolution performance in phosphate buffer 6.8


Figure 3: Dissolution performance in 0.1N HCl