View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Srinakharinwirot University: SWU e-Journals System Original Article HPMC Matrix Granule Formation: Selection of Suitable Granulating Fluid Wanwilai Darunkaisorn, Jongjan Mahadlek and Thawatchai Phaechamud* Department of Pharmaceutical Technology, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand * Corresponding author: [email protected] ABSTRACT Objective: The purpose of this study was to investigate and select the suitable granulating fluid for the matrix granules consisting of hydroxypropyl methylcellulose (HPMC). Method: Viscosity of the granulating fluids containing HPMC in different solvents was determined. The matrix granules obtained from mixing the granulating fluid with propranolol HCl, HPMC and lactose were assessed for bulk density, particle size distribution, flowability and friability. SEM, DSC, powder x-ray diffraction and drug dissolution studies were conducted to characterize the physical properties of the granules. Results: Type of granulating liquid affected the granule properties. The utilization of isopropyl alcohol as a granulating liquid and subsequently adding with water was a suitable system for agglomeration of powders. Good physical properties were obtained for the granule prepared by using this granulating fluid. Conclusion: Type of solvent and amount of water played an important role for physical properties of HPMC in the formation of the matrix granule due to the hydrophilicity and gel formation of this polymer. The use of isopropyl alcohol as granulating liquid and subsequently adding with water was a suitable process in producing the matrix granules consisting of HPMC. Keywords: hydroxypropyl methylcellulose, matrix granule, granulating fluid Thai Pharm Health Sci J 2009;4(1):29-45§ Introduction §Oral matrix system is the most popular form among effectiveness. Solid oral controlled-release dosage forms sustainable release dosage forms in terms of are available either as single-unit or multiple-unit. The effectiveness in controlling drug release and economics gastro-intestinal tract dispersion of multiple-unit dosage in manufacturing process. The matrix device consists of forms also reduces the risk of local irritation of gastric drug particles dispersed homogenously at molecular or mucosa and also promotes the drug absorption.2 particular level throughout a polymer matrix.1 Oral Multiple-unit dosage forms could be prepared in form controlled-release dosage forms are able to improve the of pellet, granule, multi-particulate and mini-tablet. patient compliance due to a reduced dosing frequency. Granule could be produced by wet and dry granulation Furthermore, these systems might provide a decrease of techniques. Addition of hydrophilic polymer as matrix incidence or intensity of the side effect, prolonged component might prolong the drug release from the therapeutic effect, as well as an increase of cost granule. Hydrophilic matrix has become extremely popular in controlling rate of drug release from solid dosage forms. Hydroxypropyl methylcellulose (HPMC) § 14th year of Srinakharinwirot Journal of Pharmaceutical Science Thai Pharmaceutical and Health Science Journal, Vol. 4 No. 1, Jan. – Mar. 2009 29 has been employed extensively as a hydrophilic matrix In this study, the assessment of the different solvent former in the oral controlled-release dosage forms for systems was performed to select the suitable granulating various drugs including propranolol HCl. Its popularity fluid for producing the propranolol HCl granule containing can be attributable to its non-toxic nature, small influence HPMC as matrix component. The characterization of of processing variables on drug release, ease of granule prepared from different solvents was carried out. compression, and capability to accommodate a high level of drug loading.3,4 Material and Methods The use of water as the granulating liquid for hydrophilic matrix compositions could give the lump Materials 5 formation , but some research claimed that water could Propranolol hydrochloride (lot no. 941002, China be employed for this purpose. Steam granulation was National Chemical Imp. Exp., China), hydroxypropyl attempted as an alternative granulation technique to methylcellulose K 15M (Methocel® K 15M) (lot no. NH 6,7 improve the dissolution of poorly soluble drug. When 16012N11, Colorcon Asia Pacific Pte. Ltd.) and the HPMC particles are exposed to the water during the Emcompress® (Mendell, Bodenheim, Germany) were granulation, a highly viscous gel layer forms around used as received. Dichloromethane (lot no. 02110176, them. The granule produced from low molecular weight Reagent Chemical Industry Ltd., Thailand), ethanol (lot HPMC using water as granulating liquid was less no. 0501252, VWR International Ltd., England), isopropyl compact with poor flowability and lower bulk density. This alcohol (lot no. K33157272, VWR International Ltd., is because this polymer had lower viscosity and thinner England) were used as granulating fluid. HCl solution (lot gel layer, which consequently promoted the lower ® 8 no. A01025, Baker Analyzed A.C.S. Reagent, USA), adhesion between particles. The poor water uptake monobasic potassium phosphate (lot no. 45-2, P.C. Drug owing to the gel-forming property of HPMC retarding the Center Co. Ltd., Thailand), sodium hydroxide pellet (lot water penetration affected the wettability of the powder 9 no. 03/07/157A) and sodium chloride (lot no. 1149, P.C. mixture and granule formation. The water uptake, gelling Drug Center Co. Ltd., Thailand) were purchased from rate and viscosity were the important factors affecting the 10 P.C. Drug Center Co. Ltd., Thailand. HPMC capsule no. granule formation. Because of high hydration and gel 1 (Capsugel, Thailand) and NP™ capsule no. 1 forming properties of HPMC after contact with water, the (Capsugel, Thailand) were used as received. sticky mass was formed and it was difficult to pass through the screen to form the granule. Therefore, this Determination Solubility Property of HPMC study wished to select the suitable solvent system for producing the granule consisting of HPMC with Solubility of HPMC in various solvents was diminishment of lump formation. determined. The solubility data were utilized to select the Propranolol hydrochloride is a β-adrenergic blocking granulating liquids for producing the granules. The agent, i.e. a competitive inhibitor of the effects of solvents used in this determination were considered catecholamines at β-adrenergic receptor sites. It is widely based on solubility and viscosity of HPMC. The used in therapeutics for the antihypertensive, anti- employed liquids were water, 95% ethanol, angorous and antiarrhythmic properties. Furthermore, dichloromethane, isopropyl alcohol (IPA), mixtures of with its short elimination half-life of 3 hours11, it is a ethanol (E) and dichloromethane (D), and mixtures of suitable model drug to be developed into prolonged IPA and water. HPMC powder (3 g) was dispersed in release dosage form. 150 ml of various liquid and stirred with magnetic stirrer for 24 hours in the closed container. The appearance of 30 Thai Pharmaceutical and Health Science Journal, Vol. 4 No. 1, Jan. – Mar. 2009 mixture was observed and then the viscosity was decrease in the granule volume. The Carr’s measured using Brookfield viscometer (Brookfield (compressibility) index was calculated from the following Engineering Laboratories Inc., USA.) (n = 3). equation: Preparation of Matrix Granules Carr’s index = tapped density – bulk density × 100 (eq. 1) tapped density 13.34-g propranolol HCl, 21.67-mg HPMC (25% of diluent) and 64.99-mg lactose (75% of diluent) were This index is interpreted in the following way: the mixed for 5 minutes using mortar and pestle. Matrix higher the compressibility index, the poorer the granules were prepared by wet granulation method. All flowability. materials were mixed in a porcelain mortar by geometric dilution and then wetted with granulating liquid in Particle Size Distribution sufficient quantity to achieve the funicular state of agglomeration. The liquids employed in wet granulation Particle size distribution was determined by sieve were water, 95% ethanol, dichloromethane, isopropyl analysis. The set of standard sieve consisted of sieves alcohol (IPA), mixtures of ethanol and dichloromethane, No. 20, 40, 60, 80, 100, 200 mesh and collection pan and mixtures of isopropyl alcohol and water. The wet respectively. Approximately 20 g of granules were put on mass was passed through a sieve No. 20 mesh and the top sieve series. The sieve series was placed on the dried in a hot air oven at 50 °C for 5 hours, then left to sieve shaker and shaken for 5 minutes. The granules cool down to room temperature. The dried granules were retained on each sieve size were weighed and calculated rescreened through the sieve No. 20 mesh. The in percentage of total weight. These values were plotted prepared granule was filled into capsule No. 1 using against particle size. capsule filling machine No. 1 (S.T.P. No.1 B.M., Thailand) which one capsule contained 40-mg Flowability propranolol HCl and 25% HPMC, and lactose 75% were The angle of repose was used to determine the used as diluent. To decrease the adhesion of the flowability of powder and granules. The angle of repose granules during dissolution test, 10% polyplasdone XL was measured from pouring the granules into a teflon was mixed with the granules and added into the