(M1030-07-41) Biorelevant Dissolution Method Considerations for the Appropriate Evaluation of Amorphous Solid Dispersions: Are Two Stages Necessary?

Purpose: Biorelevant dissolution testing has been widely used to better understand a drug or formulation’s behavior in the human gastrointestinal (GI) tract. The successful evaluation of biorelevant dissolution performance requires recognizing the importance of the biorelevant media used and the specific details of the dissolution method, especially for supersaturating amorphous solid dispersion (ASD) formulations. However, the conventional in vitro biorelevant dissolution testing conditions are always indirect and somewhat of a mismatch with the in vivo dissolution in the GI tract. The changes in media/fluid species, bile acid, ionic strength, pH, volume, and transit from the gastric to the small intestine (motility) are not able to be accurately represented in conventional testing, but could play a significant role in the in vivo human physiological system. Also, the drug properties, such as pKa, ionization, crystallization and precipitation tendency, all might have positive dissolution or negative precipitation risk impacting the dissolution in the GI tract as shown in Figure 1A. More importantly, for ASD formulations, the dissolution supersaturation involves the potential for coexistence of several different phases. Therefore, an appropriate dissolution testing tool and method with suitable media need to be determined for characterizing the biorelevant dissolution performance of ASD formulation.

Methods: Nine model drugs (Celecoxib, Efavirenz, Tolbutamide, Indomethacin, Nifedipine, Itraconazole, Dipyridamole, Ketoconazole, and Griseofulvin), as shown in Figure 1B, were selected based on their ionization properties (i.e. acid, base or neutral) and precipitation tendency (i.e. moderate or slow crystallizer) to examine the impact of drug properties on the optimal testing method for evaluating ASD dissolution performance in vitro. All drug compounds were successfully prepared as binary ASDs with 25% drug loading, by spray drying with two widely used polymers, HPMCAS-716 and PVPVA-64. Then, the single compartment 2-stage pH-shift dissolution testing has been utilized to simulate the change in pH, media composition, and transit time in the GI tract, and results were compared against the conventional single compartment 1-stage dissolution technique. Non-sink and sink conditions were utilized in the 1-stage USP dissolution and the 2-stage pH-shift dissolution to study ASD performance, as shown in Figure 2A. To verify that the 2-stage dissolution method better represented the in vivo dissolution behavior, the 3-compartment gastrointestinal simulator (GIS) was also used for nifedipine and griseofulvin ASDs to compare with the 1-stage and 2-stage dissolution performance.

Results: Overall, comparing the 2-stage pH-shift dissolution with the conventional 1-stage dissolution method, the ASD formulated with weak acid compounds did not show any difference in the small intestinal stage (second stage) between 1-stage versus 2-stage method no matter the ionized state in the small intestine, precipitation and crystallization rate, dosage amount, and enteric or aqueous soluble polymer (HPMCAS-716 and PVPVA64) in the ASD. The ASD formulated with weak bases ionized in the small intestinal pH environment and a unionized but slow crystallizer also did not display any significant difference in dissolution performance between 1-stage and 2-stage methods. However, as shown in Figure 2B-E, for weak bases that are unionized (Nifedipine) in the small intestinal pH environment or undissociated compounds (Griseofulvin) (when either are relatively fast crystallizers) can show a dramatic difference between 1-stage versus 2-stage dissolution under non-sink conditions, with no difference under sink conditions. In Figure 3A-D, The GIS results confirmed that the simple 2-stage dissolution method is a more practical high throughput tool to evaluate the supersaturation ability and precipitation tendency of the ASD formulated with the unionized weak base in the small intestinal pH and neutral compounds (relatively fast crystallizers) under non-sink conditions.

Conclusion: In general, the precipitation and crystallization tendency, ionization state in the GI tract, the polymer’s hydrophobicity in ASD, and the total dosage amount of drug are all aspects which can play significant roles in the selection of ASD dissolution methods to evaluate the supersaturation and dissolution performance. We developed a schematic flowchart to guide the biorelevant dissolution methods selection for ASD formulations, as shown in Figure 3E. This guidance could be used for optimizing the polymer selection based on the dissolution performance for the ASD formulation in the preformulation and preclinical drug discovery.

Acknowledgements: The authors declare no competing financial interest


Figure 1. (A) The schematic diagram of the dissolution pathway of the different categories of the oral dosage formulation in the human gastrointestinal (GI) tract. (B) The crystallization rate in solution, pKa values, and the theoretical dissolution pathway in the human GI tract of the drugs.


Figure 2. (A) One-stage USP dissolution vs Two-stage pH-shift dissolution. The non-sink dissolution profile of 25% unionized weak bases at pH 6.5 (Nifedipine) and neutral drug (Griseofulvin) with 75% polymers ASD in the comparison between 1-stage dissolution and 2-stage pH-shift dissolution method. (B) 75% HPMCAS716-25% Nifedipine ASD, (C) 75% PVPVA64-25% Nifedipine ASD, (D) 75% HPMCAS716-25% Griseofulvin ASD, and (E) 75% PVPVA64-25% Griseofulvin ASD.


Figure 3. The 3-compartment gastrointestinal simulator (GIS) of dissolved of the drug concentration in the duodenum and the jejunum of the (A) 75% HPMCAS716-25% Nifedipine ASD, (B) 75% PVPVA64-25% Nifedipine ASD, (C) 75% HPMCAS716-25% Griseofulvin ASD, and (D) 75% PVPVA64-25% Griseofulvin ASD. (E) The Flowchart of the Biorelevant Dissolution Method Selection.