Evaluation of a diltiazem cream preparation for estimation of degradation behavior

Year 2021, Volume: 25 Issue: 1, 13 - 21, 27.06.2025

Bahar Köksel Özgen Burcu Bulut Nagehan Sarraçoğlu Asuman Aybey Doğanay Onur Pınarbaslı

Abstract

Diltiazem cream, which is used in chronic anal fissure (CAF) treatment, is known to be susceptible to hydrolysis and degradation in aqueous solutions. The major pathway of degradation is o-deacetylation which leads to formation of 'desacetyl diltiazem' and this study focuses on this degradation mechanism. In this study, degradation of diltiazem incorporated into an oil-in-water cream base was investigated. It was especially aimed to show the effect of the formulation preparation procedure on impurity formation during the diltiazem cream formulation. In this regard, preliminary studies were performed to optimize the formulation parameters for stability. The outcome of these studies was applied to the preparation procedure; the compositions of excipients were kept constant while the order of addition of excipients to the aqueous phase and the mixing time were varied. To our knowledge, there is no study published regarding the relation between this degradation and the formulation process. Formulations were characterized in terms of formation of the desacetyl diltiazem impurity with a validated stability indicating HPLC method. The cream formulation with the highest stability was obtained through mixing propylene glycol and water first and adding diltiazem active substance in the final step of formation of aqueous phase with a shortened stirring time. This preparation procedure exhibited reduced desacetyl diltiazem impurity formation.

Keywords

Diltiazem , cream dosage form , formulation , desacetyl diltiazem impurity

References

• [1] Pereira CEDO, Nogueira FHA, Pianetti GA. Development and validation of a stability indicating HPLC method to determine diltiazem hydrochloride in tablets and compounded capsules. Braz J Pharm Sci. 2017; 53(3). [CrossRef]
• [2] Kumar BMS, Rajkamal B, Chandramowli B. A validated RP-HPLC method for the determination of diltiazem in raw material and pharmaceutical dosage form. Int J Pharm Sci Drug Res. 2018; 10(6): 487-491. [CrossRef]
• [3] Buur JL, Baynes RE, Yeatts JL, Davidson G, DeFrancesco TC. Analysis of diltiazem in Lipoderm® transdermal gel using reversed-phase high-performance liquid chromatography applied to homogenization and stability studies. J Pharm Biomed Anal. 2005; 38(1): 60-65. [CrossRef]
• [4] NICE, National Institude for Health and Care Excellence. Chronic anal fissure: 2% Topical diltiazem hydrochloride.https://www.nice.org.uk/advice/esuom3/resources/2-topical-diltiazem-hydrochloride-for-chronic-anal-fissure-pdf-17548582597 (accessed on 14 January 2020).
• [5] Shah M, Sandler L, Rai V, Sharma C, Raghavan L. Quality of compounded topical 2% diltiazem hydrochloride formulations for anal fissure. World J Gastroenterol. 2013; 19(34): 5645-5650. [CrossRef]
• [6] Dhawan S, Chopra S. Nonsurgical approaches for the treatment of anal fissures. Am J Gastroenterol. 2007; 102: 1312-1321. [CrossRef]
• [7] Diltiazem hydrochloride 2% cream leaflet. https://www.slapharma.com/wp-content/uploads/2019/07/MI-1-Anoheal-Patient-Information-Leaflet-Mar07.pdf (accessed16 January 2020)
• [8] Griffin N, Acheson AG, Jonas M, Scholefield JH. The role of topical diltiazem in the treatment of chronic anal fissures that have failed glyceryl trinitrate therapy. Colorectal Dis. 2002; 4(6): 430-435. [CrossRef]
• [9] Alexandre Miguel VAR, Isabel Maria CDA. Stable diltiazem hydrochloride pharmaceutical composition for cutaneous application and process for the preparation thereof. EP Patent 1516622 A1; 2003.
• [10] Conjeevaram R, Dubash D, Salpekar A. Topical pharmaceutical compositions comprising calcium-channel blocker and method of using same. WO Patent 2008/022032 A2; 2007.
• [11] Risaliti L, Piazzini V, Di Marzo MG, Brunetti L, Cecchi R, Lencioni P, Bilia AR, Bergonzi MC. Topical formulations of delta-aminolevulinic acid for the treatment of actinic keratosis: Characterization and efficacy evaluation. Eur J Pharm Sci. 2018; 115: 345-351. [CrossRef]
• [12] European Pharmacopeia 7.0. Efficacy of antimicrobial preservation, European Department for the Quality of Medicines within the Council of Europe, Strasbourg, section 5.1.3, 2009:528–9