(W0930-08-48) Development of a Controlled-Release Diphenhydramine HCL Tablet Using HPMC-Based Hydrophilic Matrix Technology

Purpose: Diphenhydramine Hydrochloride is widely used in immediate-release OTC medications for allergy relief however, its role as a sleep aid benefits from a controlled-release system that maintains therapeutic plasma levels throughout the sleep cycle. This study presents the development of a hydrophilic matrix tablet (Diphenhydramine HCL 15MG) utilizing Hydroxypropyl Methylcellulose (HPMC) to achieve sustained drug release over six hours of sleep cycle. The release mechanism is governed by matrix swelling and diffusion upon hydration by gastrointestinal fluids, HPMC forms a gel barrier through which Diphenhydramine diffuses. As the outer matrix erodes, inner layers hydrate, ensuring continuous drug release. Optimization of HPMC particle size distribution was critical to modulating release kinetics and preserving matrix integrity. Spray-dried Lactate Monohydrate was incorporated as a binder, while Microcrystalline Cellulose (CPE) enhanced powder flow and blend uniformity. The formulation supports direct compression and demonstrates favorable tablet characteristics, including flowability, compressibility, weight uniformity, and mechanical strength. These findings align with previous studies demonstrating the effectiveness of HPMC-based matrices in sustaining Diphenhydramine release profiles^{1 2}, establishing a robust platform for sleep aid applications.

Methods: HPMC (Headcel® 75HD4000 CR) particle size distribution was assessed using Microtrac S3500 Laser Diffraction Analyzer (Table 1). Individual powders for all three formulas as given in the formula table (Table 1) measured on a Mettler Toledo Precision Balance and blending was performed using Hauschild Speed Mixer (1200 RPM for 2 minutes) to ensure homogeneity. Powder flow properties including Tap density and Compressibility were assessed per USP-NF < 616 > (Table 1). Tablets were manufactured via direct compression using Korsch STYL’One Nano Simulation Compactor with Main Compression Force (30kN) and “0” Shock Frequency (Hz) targeting (8 mm round, 300 mg weight, 80 to120 N hardness) tablets. Friability was determined using a Sotax FT2 Friability Tester (Table 1). Tablet weight (n=6) was measured using a Mettler Toledo Precision Balance, and hardness (n=6) was tested using a Sotax MT50 Hardness Tester (Table 2). Data analysis done using statistical software JMP. Final tablets from Formula 2 were selected for Dissolution testing as they exhibited consistent results for both weight and hardness. USP < 711 > method used on SOTAX AT Xtend system with phosphate buffer as the medium. Three samples each tested for paddle method and basket method at different time points (2hr, 4hr and 6hr). At each time point samples were collect through filter (0.45microns) and High-performance liquid chromatography (HPLC) analysis was conducted using an Agilent 1100/1200 Series system equipped with a Gemini 5 µm C18 column, UV detection at 220 nm, and a flow rate of 1.0 mL/min. Data collected and dissolution times were calculated (Table 3).

Results: The particle size distribution of HPMC (Headcel® 75HD4000 CR) met the required specifications, confirming its appropriateness for controlled-release applications. All three formulations demonstrated favorable compressibility indices (Table 1), indicating good flow and compaction characteristics suitable for direct compression. Formulations 1 and 2 exhibited minimal variability in both tablet weight and hardness (Table 2), reflecting high manufacturing consistency. While formula 3 showed slight variation in weight, it remained within acceptable specification limits. All formulations produced tablets with uniform texture and appearance. Tablets tested using the paddle method (N=3) showed inconsistent release due to adherence to the vessel bottom. In contrast, the basket method (N=3) yielded consistent and expected dissolution profiles, confirming the controlled-release behavior. The dissolutions times were as expected and reached maximum values at 6hrs time point (Table 3) with sharp peak of DPH at all time points.

Conclusion: The formula 2 comprising HPMC (Headcel® 75HD4000 CR) at 20% with Lactose Monohydrate, and MCC exhibited excellent compatibility and manufacturability. This combination with disintegrant Kovidone worked well to deliver the expected performance for controlled release application. The final tablets demonstrated favorable compressibility, consistent weight distribution, and strong mechanical properties, including optimal hardness and low friability. Additionally, the formulation provided dependable controlled-release performance at given time points and matched with the half-life (6hrs) of the Diphenhydramine HCL. Owing to its versatility, this matrix system is well-suited for active pharmaceutical ingredients (APIs) with a broad range of solubility characteristics, making it a promising platform for extended-release drug development.

References: 1: Akkaramongkolporn, P., Ngawhirunpat, T., & Rojanarata, T. (2010). Effect of cation exchange resins on physical properties and drug release of diphenhydramine HCl matrix tablets. Drug Development and Industrial Pharmacy, 36(2), 206–213. https://doi.org/10.3109/03639040903050266
2 Formulation and Evaluation of Hydroxypropyl Methylcellulose-based Controlled Release Matrix Tablets for Theophylline. T. Raja Sekharan*, S. Palanichamy, S. Tamilvanan 1, S. Shanmuganathan 2. And A. Thanga Thirupathi 3

Formulas table and quality metric

Tablets Hardness and Weight summary

Dissolution Testing and HPLC traces