Water-sorption behavior of some commonly used pharmaceutical excipients: Microcrystalline cellulose (MCC), Hydroxypropyl methylcellulose (HPMC) and Croscarmellose Sodium 1 A Ravikiran, 2 M Arthanareeswari, 3 P Kamaraj, 4 Ch Praveen, 5 K V Pavan Department of Chemistry, Faculty of Engineering & Technology, SRM University, Kattankulathur, Tamil Nadu, Pin 603203, India, Email: 1 ravianalytical@gmail.com [Received: 29 th Jan.2015; Revised: 11 th Feb.2015; Accepted:12 th Feb.2015] Abstract Physical properties of excipients used in formulations play a significant role in terms of processability, efficacy, and thereby, quality. Generally, as far as physical properties are concerned, pharmaceutical active ingredients are paid much more attention than that of excipients. But, excipients do undergo physicochemical changes when subjected to different process operations, handling and storage conditions. The physicochemical changes of excipients may have an impact on product quality consistency. In recent years, all the international drug regulatory authorities have strongly insisted to ensure consistent product quality using all possible control measures. In the current study, Dynamic Vapor Sorption (DVS) analysis, Powder X-Ray Diffraction (PXRD) and Differential Scanning Calorimetry (DSC) studies have been employed to understand the physical changes of microcrystalline cellulose, Hydroxypropyl methylcellulose and Croscarmellose sodium when subjected to different environmental conditions for different durations. The kinetics derived from isotherms and other results would help the formulation scientists to optimize process and storage conditions of the said excipients. I. INTRODUCTION According to ICH (International Conference of Harmonization) guidance Q1 Stability storage conditions [1], there are totally four climatic zones, namely Zone I, Zone II, Zone III and Zone IV. And, there are four stability conditions specified viz. 25 C-60%RH, 30 C-65%RH, 30 C-75%RH and 40 C- 75% RH. In general, shelf-life of pharmaceutical products is calculated based on available stability data in different conditions as mentioned above. Details of the stability studies are out of scope of this work; however one may refer ICH guidance for the same. In the current work, water sorption behavior at different ICH stability conditions and corresponding physical changes of microcrystalline cellulose, hydroxypropyl methylcellulose and croscarmellose have been studied. Microcrystalline cellulose (MCC), owing to its excellent flow and mechanical properties, is the most versatile excipient employed in pharmaceutical formulations. MCC serves a variety of purposes, such as a binding agent, diluent, bulking agent, anti-caking agent, disintegrant and emulsifier. There were some previously reported studies regarding impact of moisture content on mechanical properties of MCC [2-3]. A number of manufacturers supply MCC under various trade names like Avicel, Vivapur, Ceolus, etc. For the purpose of current study, a free-flowing, directly compressible grade of MCC, i.e., Avicel PH 102 has been employed. Hydroxypropyl methyl cellulose (HPMC) or Hypermellose, is a synthetic modification of the natural polymer. Due to its solubility characteristics, stability, flexibility and chip resistance properties, it is widely used in different kinds of formulations like immediate release or controlled release [4-6]. Croscarmellose sodium (CCS) is a cross-linked sodium carboxy methylcellulose, commonly used as a superdisintegrant in pharmaceutical dosage forms. It is also used in food industry. It is used as a swelling agent in formulations to allow faster disintegration and dissolution rate and thus bioavailability [6-7]. Ability of a substance to attract and adsorb or absorb moisture from air or surrounding environment is called hygroscopicity. Hygroscopicity is a common property in all of the above discussed three excipients. Hygroscopic materials gain weight when exposed to moisture. The gained water changes the very physical characteristics of the material. Hence, the objective of the current work is to understand the rate of weight gain / moisture uptake when the materials are exposed to the four different stability conditions, i.e., 1) 25 C-60%RH, 2) 30 C- 65%RH, 3) 30 C-75%RH and 4) 40 C-75% RH; these conditions henceforth called as Condition I, II, III and IV respectively. Powder X-Ray Diffraction (PXRD) and Vapor sorption analysis (VSA) techniques were used to carry out this study. The PXRD is very well known technique used for qualitative and quantitative evaluation of solids [9-11], in the current study PXRD is used to check the nature of the material used. The VSA instrument has the ability to measure the weight changes in a chamber, where 52
temperature and relative humidity are programmable. The resultant isotherms are processed to understand the moisture uptake pattern. VSA is also a well known technique used for absorption and desorption kinetics and further to investigate surface properties [12-13]. A. Materials. II. EXPERIMENTAL The materials, MCC, HPMC and CCS were obtained from Sigma-Aldrich (St Louis, MO). The materials are used as obtained without any further treatment. B. Methods. 1) Powder X-Ray Diffraction (PXRD): X-Ray diffraction profiles of the samples of MCC, HPMC and CCS were collected using Rigaku Ultmia s Powder X-Ray Difftactometer. Each sample was scanned in the range of 3 to 45 2theta., with a step size of 0.02 2theta and time per step of 0.1 sec. Scintillation counter was employed as the detector. 2) Vapor Sorption Analysis: The sorption study program was designed in such a way that, each sample got initially subjected to desorption / drying at 40 C- 0%RH, and was subsequently sujected to deired conditions (I, II, III and IV) until the sample achived a stable weight. Diagramatic representation of the study design is represented in Fig. 1. Instrument TA s Q500 was used to conduct this study. Silicified quartz crucibles were used for the analysis. The weight loss observed at the initial drying stage indicates that the saturated amount of water present with the material upon stoarage of the same at ambient conditions. One must note that the rate of water-sorption depends upon not only humidity present but also the temperature. Usually formulation blends are studied for hold time stability, In such cases scientists may refer the below represented 25-60% RH data to understand probable extent of water uptake and the changes that may occur in average weight or potency of the blend. The remaining other three conditions data are useful to see water uptake during stability conditions or shortterm extrusions. For certain tablet formulations disintegration time and hardness might change with the up-taken water during stability conditions exposure. Fig. 2 Isotherm of MCC, studied for 25 C-60%RH. Fig. 1. Schematic representation of study design III. RESULTS AND DISCUSSION: 1.Powder X-Ray Diffraction (PXRD): X-Ray diffraction profiles of initial samples of MCC, HPMC and CCS were represented in Figs. 2, 3 and 4 respectively. The patterns confirm that these compounds are not crystalline. 2.Vapor Sorption Analysis: The vapor sorption isotherms of different conditions of each of those three excipients are depicted in Figs. 2 to 13 respectively. As each sample was heated to dryness prior to subjecting to respective stability condition, each isotherm shows a drying stage and sorption stage. Table 1 provides the amount of total weight gain and time taken, at each condition for each excipient. From the results in the table, it is evident that the absorption is very specific to the condition and duration. Fig. 3 Isotherm of MCC, studied for 30 C-65%RH. Fig. 4 Isotherm of MCC, studied for 30 C-75%RH. 53
Fig. 5 Isotherm of MCC, studied for 40 C-75%RH. Fig. 9 Isotherm of HPMC, studied for 40 C-75%RH. Fig. 6 Isotherm of HPMC, studied for 25 C-60%RH. Fig. 10 Isotherm of CCS, studied for 25 C-60%RH. Fig. 7 Isotherm of HPMC, studied for 30 C-65%RH. Fig. 11 CCS, studied for 30 C-65%RH. Fig. 8 Isotherm of HPMC, studied for 30 C-75%RH. Fig. 12 CCS, studied for 30 C-75%RH.. 54
Material Fig. 13 CCS, studied for 40 C-75%RH. TABLE 1. SORPTION RESULTS SUMMARY 1 Condition wise results for each excipient Condition Total weight gain* (% w/w) Time taken** (Min) MCC 25 C-60% RH 6.3 91 30 C-65% RH 6.5 68 30 C-75% RH 7.7 84 40 C-75% RH 7.1 73 HPMC 25 C-60% RH 8.3 139 30 C-65% RH 9.1 125 30 C-75% RH 12.1 139 40 C-75% RH 10.9 73 CCS 25 C-60% RH 13.0 185 30 C-65% RH 14.4 247 30 C-75% RH 19.5 241 40 C-75% RH 18.3 189 *The weight gain calculated from dried stage, percent weight gain over dried material s weight. ** The time taken to complete the weight gain process from the dried state. This calculated time is very much approximate, and it is very important to notice that the sorption was not linear. IV. CONCLUSION Moisture absorption behavior of excipients may affect drug assay (potency) and related substances in a formulation. Apart from this, the physical and chemical properties of the formulation such as hardness, flowability, tabletability and disintegration time, etc. may also get affected by the moisture content. In the current work, studies were conducted on three commonly used excipients (MCC, HPMC and CCS). Absorption behavior of these excipients were evaluated under four conditions (25 C-60%RH, 30 C-65%RH, 30 C-75%RH and 40 C-75% RH), these are the conditions generally used to establish expiry date (Shelf life) for pharmaceutical products. The results of this current work indicate that the absorption behavior is unique at each condition for the given excipient. The results obtained in this work can readily be used by pharmaceutical scientists to design a particular dosage form, to choose proper packaging configuration, to understand water activity, to identify causes of hydrolytic degradations of the drug present along with these excipients, and to choose process and operational conditions appropriately. Especially, for those formulations involving these excipients, the blend hold time and conditions can be optimized based on these results. V. REFERENCES [1]. W. Grimm, Extension of the international conference on harmonization tripartite guideline for stability testing of new drug substances and products to countries of climatic zones III and IV, Drug Dev. Ind. Pharm., vol. 24, pp. 313-325, January 1998. [2]. G. E. Amidon, and M. E. Houghton, The effect of moisture on the mechanical and powder flow properties of microcrystalline cellulose, Pharm. Res., vol. 12, pp. 923-929, June 1995. [3]. K. A. Khan, P. Musikabhumma, and J. P. Warr, The effect of moisture content of microcrystalline cellulose on the compressional properties of some formulations, Drug Dev. Ind. Pharm., vol. 7, pp, 525-538, January 1981. [4]. J. Siepmann, and N. A. Peppas, Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC), Adv. drug deliver. rev., vol. 48, pp. 139-157, June 2001. [5]. G. Xu, and H. Sunada, Influence of formulation change on drug release kinetics from hydroxypropylmethylcellulose matrix tablets, Chem. Pharm. Bull., vol. 43, pp. 483-487, March 1995. [6]. T. Loftsson, H. Friðriksdóttir, S. Thórisdóttir, and E. Stefánsson, The effect of hydroxypropyl methylcellulose on the release of dexamethasone from aqueous 2-hydroxypropyl-β-cyclodextrin formulations Int. j. Pharm., vol. 104, pp 181-184, April 1994. [7]. C. Ferrero, N. Munoz, M. V. Velasco, A. Muñoz- Ruiz, and R. Jiménez-Castellanos, Disintegrating efficiency of croscarmellose sodium in a direct compression formulation, Int. J. Pharm. vol. 147, pp. 11-21, February 1997. [8]. N. Zhao, and L. L. Augsburger, The influence of product brand-to-brand variability on superdisintegrant performance a case study with croscarmellose sodium, Pharm. Dev. Technol. vol. 11, pp. 179-185. January 2006. [9]. A. Ravikiran, M. Arthanareeswari, P. Kamaraj, C. Praveen, and K. Pavan, A robust method for simultaneous quantitative determination of Eplerenone polymorphs in tablet formulation by 55
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