(M1130-08-54) Investigating the Cause of Dissolution Failure of a Highly Soluble Pharmaceutical Salt Form of a Molecule

Purpose: Pharmaceutical salts are a long-established, well-known, and widely accepted method for improving the solubility, stability, purity, bioavailability, and manufacturability of drug molecules, provided the molecule has an ionizable functional group. Once the final salt form with the desired physicochemical properties is identified, it quickly moves through various stages of drug development before being formulated into a final dosage form. It is rare for a highly soluble salt form to fail to achieve the desired dissolution profile once formulated as a capsule or tablet. This case study presents investigations into the most common pharmaceutical salt form of a molecule that is highly soluble in buffers but struggled to meet the desired dissolution profile.

Methods: The active pharmaceutical ingredient (API) used here was in the form of a monohydrate sodium salt (Na⁺), crystalline with a melting temperature below 200 °C and moderately hygroscopic (Ph.Eur.). A solubility of 0.4 mg/mL in Fasted State Simulated Intestinal Fluid (FaSSIF, pH 6.5) was reported. The human estimated dose (HED) was determined to be about 100 mg. The API crystal had rod shaped morphology with a D90 of ~80 µm, bulk and tapped density of 0.15 and 0.19 g/mL respectively and a Hausner Ratio of 1.30 along with Carr’s Index of 22%. To enhance the flow properties, granules were prepared by roller compaction. Several tablet formulations were trialled using excipients such as diluents, disintegrant, glidant and lubricants etc., generally used for tablet formulations. Dissolution behaviour of the API (powder), API compact (API only tablet), formulated tablet and granules filled in capsule was monitored in 500 mL Phosphate buffer pH 6.8 using Agilent 708 DS dissolution bath USP II apparatus, equipped with 850 DS auto sampler. The media was heated at 37±0.5 °C under a stirring speed of 75 RPM. Additional investigations such as compression induced polymorphic change by XRPD analysis, salt disproportionation by Raman spectroscopy and surface analysis using scanning electron microscope and energy-dispersive X-ray spectroscopy (SEM/EDS) was also performed on the API (only) compacts/tablets, to fully understand and identify the impact of compaction if any.

Results: A fit-for-purpose, phase-appropriate tablet formulation of the API in the form of a sodium salt monohydrate was manufactured. However, a zero order dissolution profile was obtained irrespective of several modifications to the formulation process, different combinations, level and types of excipients (including water soluble diluents) utilised. Dissolution profiles of the granules filled in capsule was also evaluated but showed no improvement. Interestingly, a rapid dissolution was observed upon sprinkling granules directly into the dissolution vessel. This led to investigations to determine the impact of compaction on the physical properties of the API. Results showed no changes to the physical form of the API nor did the salt undergo disproportionation upon compaction. However, SEM/EDS results showed Na⁺ ions migrating/aligning to the surface of the compacts. Similarly, SEM/EDS of this compact post dissolution showed presence of Na⁺ ions on the collapsed undissolved compact surface. This suggested that the presence of Na⁺ ions on the surface of the compact was potentially preventing or slowing the dissolution due to potential hydrogel formation. Further, literature research suggested that sodium salts are known to have kosmotropic properties that can increase hydrophobic effects in aqueous solutions by promoting hydrogen bonding thereby promoting formation of a gel like layer. Formation of such a gel like layer (hydrogel) around the tablet could significantly inhibit disintegration that resulted in a zero-order dissolution profile. Wetting agents are known to disrupt such hydrogel formations and hence upon incorporating a surfactant such as sodium lauryl sulphate (SLS) into the blend significantly improved the dissolution profile upon encapsulation.

Conclusion: The study revealed that poor disintegration and hence slower dissolution of the oral solid dosage form was primarily due to hydrogel gel formation on the surface, a consequence of the kosmotropic property of Na⁺ ions. This issue only exacerbated upon encapsulation and amplified further upon tabletting. While the incorporation of a wetting agent significantly improved dissolution rates, such agents are typically not included for highly soluble compounds, which can delay drug product development. These findings underscore the need for keen observation of the dissolution process and the inclusion of surfactants during excipient screening in the development phase proactively to prevent potential delays to development timeline.

References: Naseem, B., Arif, I. and Jamal, M. A. 2021. Kosmotropic and Chaotropic Behaviour of Hydrated Ions in Aqueous Solutions in Terms of Expansibility and Compressibility Parameters. Arabian Journal of Chemistry. Volume 14, (Issue 11), Article 103405.

Figure 1 SEM/EDS image of the API (Na+) compact/tablet