(T1430-09-57) From Miscibility Modeling to Performance: Developing Stable ASD Granules of Nifedipine Using Poloxamer and Copovidone

Purpose: Poloxamers are a class of multifunctional excipients widely recognized for their amphiphilic nature, enabling them to serve as solubilizers, stabilizers, and drug delivery enhancers in pharmaceutical formulations. Chemically, poloxamers are triblock copolymers composed of a central hydrophobic block of polypropylene oxide (PPO) flanked by two hydrophilic blocks of polyethylene oxide (PEO). The ratio and length of these blocks determine their molecular weight, hydrophilic-lipophilic balance (HLB), and functional behavior in formulations. Poloxamer 188 (P-188) has a higher PEO content, making it more hydrophilic, whereas Poloxamer 407 (P-407) has a larger PPO core, contributing to its thermogelling (at >15% concentration) and micelle-forming capabilities. In addition to poloxamers, copovidone (a copolymer of vinylpyrrolidone and vinyl acetate) is another versatile polymer that has shown excellent performance in amorphous solid dispersion (ASD) systems. Its ability to inhibit drug crystallization and enhance dissolution makes it a valuable component in solubility enhancement strategies. In this study, we aim to explore P-188, P-407 and copovidone to develop ASD granules of nifedipine, a poorly water-soluble and flowable drug. The objective was to prepare formulation using a non-aqueous granulation method, and evaluate the solubilization potential and performance of the resulting system. 

Methods: Nifedipine (Letco Medical, LLC) properties were analyzed using an algorithm-based tool (ZoomLab®) to determine the miscibility force (MPa0.5) for poloxamers and copovidone by utilizing the various equations (Table 2). The following properties of Nifedipine: contribution from dispersion forces (δd) = 20.25 MPa 0.5, contribution from dipolar forces (δp) = 6.03 MPa 0.5, contribution from hydrogen bonds (δh) = 8.73 MPa 0.5. Nifedipine formulations were prepared by non-aqueous granulation using ethanol (200 proof) and the excipients listed in Table 1. Nifedipine, P- 407 (Kolliphor® P 407), copovidone (Kollidon® VA 64), a co-processed excipient (Ludipress®), and crospovidone (Kollidon® CL-M) were first passed through a #40 mesh sieve to break up any agglomerates. The sieved materials were then blended using a mortar and pestle. Ethanol (~35% w/w) was gradually added to the mixture and manually mixed with the pestle to form wet granules. The resulting granules were dried in a vacuum oven at 40 °C for 2–4 hours. Dissolution testing of granules in capsules was performed using a USP Type II apparatus (Erweka GmbH) in 1000 mL 0.1N HCl maintained at 37 ± 0.5 °C with a stirring speed of 100 rpm. The melting point (Tm) of pure Nifedipine and the glass transition temperature (Tg) of Nifedipine loaded granule formulations were measured with differential scanning calorimetry (DSC). The samples were first melted at 110 °C for 5 minutes, then heated to 200 °C, cooled down to 10 °C, and finally reheated to 200 °C. 

Results: The ZoomLab® app ranked polymers for the formulation of ASD based on differences in their Hansen solubility parameters using two methods. In practical scenarios, the solubility of a drug in polymers is influenced by various factors such as ingredient purity, water content, temperature, viscosity, and hydrogen bond interactions. Consequently, the algorithm-based model provided only a qualitative ranking of drug-polymer miscibility. Generally, miscibility is considered favorable if the result value is below 5.0 MPa0.5. Based on these results, P- 407 and copovidone were selected for non-aqueous granulation (Table 1 and Tablet 2). During the process, the drug was dissolved in ethanol and subsequently stabilized by P-407 or copovidone during drying, resulting in the formation of the ASD formulation. Dissolution studies (Figure 1A) indicated that copovidone-based and P-407-based granules increased drug solubilization (6.0- and 6.3-fold, respectively) compared to the free drug. DSC analysis showed no observable melting peak for the drug in the granules. A similar glass transition temperature (Tg) was observed for both the P-407 and copovidone-based formulations, approximately 91 °C and 94 °C, respectively (Figure 1B). However, a melting temperature was detected around 50 °C for the P-407 based formulation, consistent with the known melting range of P-407 (53–57 °C), while no melting point was observed for the copovidone-based formulation below 90 °C. This suggests that copovidone-based matrices may provide greater thermal stability than those based on P-407, particularly during long-term storage at elevated temperatures, as P-407-based matrices are more prone to melting at relatively low temperatures.

 

Conclusion: The present study successfully demonstrated the potential of poloxamers and copovidone in enhancing the solubility of nifedipine through the development of ASD granules using a non-aqueous granulation method. Algorithmic predictions using ZoomLab® indicated favorable miscibility between nifedipine and both the selected polymers—Poloxamer 407 and copovidone—based on Hansen solubility parameters. Experimental results confirmed that both excipients significantly improved drug dissolution, with copovidone- and poloxamer-based granules showing 6.0- and 6.3-fold increases, respectively, compared to the pure drug. Overall, this study highlights the effectiveness of polymer selection using the algorithm tool and a formulation strategy in improving the solubility and stability of poorly water-soluble drugs like nifedipine.

Acknowledgements: No public funds supported this work. The authors have no conflicts of interest to disclose.


Table 1: Type of Nifedipine loaded formulation and compositions.


Table 2: Miscibility force (MPa) for nifedipine and excipients (P-407, P-188 and copovidone) (calculated by ZoomLab®)


Figure 1. A) Dissolution of Nifedipine API and granules (various ratio of drug to excipients) in 0.1 N HCl; B) Melting point and glass transition temperature of Nifedipine and different granule formulations.