(M1230-03-21) Should Amorphous Dispersions Always Be Used as a Formulation Development Strategy?

Purpose: Amorphous dispersions are well known and most popular choice of technology to improve the kinetic solubility and thereby drug absorption, which is evident from the growing number of solid dispersions formulation introduced to the market in recent years. Achieving high kinetic solubility is particularly significant in case of drugs with narrow absorption window or can also be used to overcome poor drug absorption due to high intestinal drug efflux in many cases. However, as one size doesn’t fit all it is extremely important to understand the problem statement based on the detailed and highest quality physicochemical data available on the drug substance. The purpose of this study was to evaluate the feasibility of using a physical mixture of API and Polymer (generally used in preparation of ASD) to achieve complete/higher dose dissolution.

Methods: The active pharmaceutical ingredient (API) used here was highly crystalline with a melting temperature below 200 °C and moderately hygroscopic (Ph.Eur.). The drug had moderate permeability and high efflux ratio. The HED was determined to be about 1000 mg. A solubility of 4 mg/mL and 0.3 mg/mL in Fasted State Simulated Gastric Fluid (FaSSGF, pH 1.6) and Fasted State Simulated Intestinal Fluid (FaSSIF, pH 6.5) respectively, was recorded. Although it was possible to achieve high API solubility (up to 4 mg/mL) at lower pH conditions, the API precipitated out as an oil under high pH ( >5) conditions. Therefore, the challenge was to maintain a solubility of 2 mg/mL post gastric emptying. Immediate release polymers such as PVP, HPMC, PVP/VA 64, HPC, Eudragit^® EPO and Soluplus^® were initially screened for their precipitation inhibition tendency. For this, the stock solution of the API and each polymer (prepared separately) in FaSSGF were mixed in equal ratios. These stock solutions were then diluted with equal volumes of FaSSIF (pH 5.6 and 6.5 separately) to target a drug concentration of 2 mg/mL at 37 °C. Precipitation tendency was monitored for a period of 60 min post dilution. The performance of polymers that delayed or prevented drug precipitation were further evaluated by a two-stage biorelevant dissolution. Dissolution behaviour of the API (alone) as well as API and polymer physical mixture (1:1 and 1:2) was monitored in 250 mL simulated gastric and intestinal media under fasted conditions using ERWEKA DT 126 light manual dissolution bath USP II apparatus. The media was heated at 37±0.5 °C under a stirring speed of 75 RPM. The physical mixtures were subjected to a pH environment designed to simulate GI exposure: exposure to FaSSGF for 30 min, followed by incremental exposure to pH 5.6, 6.0 and 6.5, achieved via the addition of 250 mL of concentrated FaSSIF.

Results: It was clear from the dissolution profiles, that PVP/VA 64 helped in dissolving higher amount of API in solution. The API solubility was also directly proportional to the amount of polymer present in the physical mixture.

Conclusion: Evaluating the use of simple physical mixture of the polymer and API can help in circumventing the need for an amorphous solid dispersion, thereby saving valuable time, resources, and API.

References: Rumondor, A. C.F., Dhareshwar, S. S. and Kesisoglou, F. 2016. Amorphous Solid Dispersions or Prodrugs: Complementary Strategies to Increase Drug Absorption. Journal of Pharmaceutical Sciences. Volume 105, (Issue 9), Pages 2498-2508

Figure 1 Dissolution profile at 1g dose with 1:1 and 1:2 ratio of API to PVP/VA 64 as well as API alone