(T1230-05-26) Low Nitrite-Controlled Release Formulations for Water-Soluble Drugs

Purpose: The purpose of the study was to develop a safe and robust controlled release matrix tablet formulation for active pharmaceutical ingredients (APIs) with vulnerable amines. Nitrite impurities in excipients are potential sources of nitrosating agents that may contribute to the formation of N-nitrosamine from vulnerable amines like secondary amines in drug products. The rate and extent of N-nitrosamine formation depend on the solubility of the amine, level of nitrite, pH (acidity) of water layers within the drug product and manufacturing process.¹ The rank order of N-nitrosamine risks in medicines (EFPIA, 2022) was reported as amorphous > wet granulation > direct compression > dry blends.¹ Given the potential role of nitrites in excipients and the processing mode play in the formation of N-nitrosamines in drug products, it is therefore helpful to consider a holistic nitrosamine mitigation approach. Hence, using low nitrite excipients and possibly dry processing modes like direct compression (DC) would be beneficial in developing oral solid formulations. As compared to various granulation processes, a DC process is also advantageous in supporting sustainability initiatives. The objective of this study was to develop robust matrix tablet formulations via a simple direct compression method utilizing a commonly used grade of microcrystalline cellulose (MCC) and or a low nitrite (LN) grade of MCC to assess the physical properties and performance of the resulted tablets. The selected LN grade of MCC had a spec limit of nitrite for less than 200 ppb.²  Hydroxypropyl methylcellulose, (HPMC, hypromellose), was selected as the release rate controlling polymer. Two viscosity grades were studied: a particle engineered grade  suitable for direct compression process and a typical grade for controlled release (CR) application.^3,4 The latter features as a slightly higher viscosity (111,000 mPa*s vs. 151,000 mPa*s) grade. Phenylephrine hydrochloride (HCl) was selected as a model drug with vulnerable amine. Duration of drug release was targeted for 24 hours with approximately 50% release in 4 hours.

Methods: Matrix tablet formulations consisted of 30% w/w phenylephrine HCl as model drug, 30% - 60% w/w hypromellose (METHOCEL™ K100M DC2 or METHOCEL™ K200M CR) as a release rate controlling polymer, 8.5% - 38.5% w/w microcrystalline cellulose (Avicel^® PH-102 LN or Avicel^® PH-102) as filler, 0.5% w/w colloidal silica (SiO2, Cab-O-Sil^®) as anti-adherent and 1% w/w magnesium stearate as lubricant. Each formulation was compressed into 400 mg tablets on a compaction simulator using a standard round concave punch tooling. The resulting matrix tablets were evaluated for physical properties and drug release. Tensile strength (TS) of tablets were calculated and tablets with TS of approximately 1.5 MPa - 2 MPa selected for further comparison studies. Biorelevant dissolution testing was carried out on n=6 tablets using USP apparatus 2 at 50 rpm in simulated Intestinal fluid (SIF), pH 6.8.

Results: Tabletability of formulation blends containing 30% to 60% METHOCEL™ K100 DC2 are shown in figure 1. In these formulations Avicel^® PH-102 LN concentration is from 38.5% to 8.5%, respectively. It is shown, as the level of  the MCC decreases (HPMC increases), tablet tensile strength decreases. Effect of viscosity grade of HMPC on the blend compactability is shown in figure 2.  Two formulation blends containing 60% of METHOCEL™ K100 DC2 or METHOCEL™ K200M CR were compared at three compression forces. It’s shown that the CR grade of HPMC was more compactable than the particle engineered grade, METHOCEL™ K100M DC2. The interplay between flowability and compactability has been investigated before.⁵ Figure 3 shows comparative release profiles of phenylephrine from tablets containing 30%-60% METHOCEL™ K100M DC2. The highest concentration of HPMC, 60%, provided the slowest release profile matching our target of 50% release in 4 hours. This profile was also similar to the release profile from tablets containing the same concentration of METHOCEL™ K200M CR. Considering the similarity in release profiles, the formulation containing the particle engineered HMPC (METHOCEL™ 100M DC2) was selected as the prototype in our study and compared with the respective tablet containing a common grade of MCC, Avicel^® PH-102. Both formulations performed similarly and there were no significant differences between their release profiles (Figure 3).

Conclusion: A particle engineered grade of hypromellose (METHOCEL™ K100M DC2) and a low nitrite grade of MCC (Avicel^® PH-102 LN) with inherently good flow properties were successfully employed in manufacturing matrix tablets via a simple direct compression method. Two robust matrix tablet formulations for phenylephrine HCl, a soluble model drug, were studied in parallel for evaluation of the effect of low nitrite grade of MCC on tablet properties. Both formulations demonstrated high tablet tensile strength, low tablet friability, and great blend flow properties. The phenylephrine HCl release profile from both matrix tablets were similar. It was demonstrated that low nitrite MCC may be successfully used in matrix tablet manufacturing in an effort to mitigate nitrosamine formation via a direct compression process.

References: 1. Justin Moser et all., N-Nitrosamine Formation in Pharmaceutical Solid Drug Products: Experimental Observations, Journal of Pharmaceutical Sciences (2023), Doi: https://doi.org/10.1016/j.xphs.2023.01.027
2. Koudi Zhu et all., Parts per billion of nitrite in microcrystalline cellulose by ion chromatography mass spectrometry with isotope labeled internal standard: Journal of Pharmaceutical and Biomedical Analysis (2023) Volume 235, Doi: https://doi.org/10.1016/j.jpba.2023.115648
3. Nitrite content in hydroxypropyl methylcellulose https://pharma.iff.com/fileadmin/user_upload/Editor/Images/Products/Dietary_Supplements/METHOCEL_TM_/Methocel_Nitrite.pdf
4. METHOCEL cellulose ether https://pharma.iff.com/fileadmin/user_upload/Editor/Documents/METHOCEL_OVERVIEW_BROCHURE.pdf
5. Comparative Evaluation of the Powder and Tableting Properties of Regular and Direct Compression Hypromellose from Different Vendors Pharmaceutics 2023, 15(8), 2154; Doi:https://doi.org/10.3390/pharmaceutics15082154


Figure 1. Tabletability of phenylephrine HCl formulations containing various level of HPMC and low nitrite grade of MCC


Figure 2. Tabletability of phenylephrine HCl formulations containing two viscosity grades of HPMC


Figure 3. Comparative release profiles of phenylephrine HCl formulations containing 30% —60% METHOCEL™ with MCC and or LN MCC