Research Article, J Pharm Drug Deliv Res Vol: 5 Issue: 6
The Influence of HPMC Viscosity and %HPC Content as FRC Parameter on the Release of Highly Soluble Drug from Hydrophilic Matrix Tablets
| Himankar Baishya*, Zhou Yangxing, Wangshengmin and Lin Shao Hui | |
| Department of Formulation Development, Beijing Sciecure Pharmaceuticals Co., Ltd., Beijing, China 101301 | |
| Corresponding author : Himankar Baishya Senior Director, Research and Development Department, Beijing Sciecure Pharmaceuticals Co., Ltd., North Shi Zhen in the North industrial area, Shunyi district, Beijing, China-101301 Tel: +861060447688/ 8356 E-mail: himankar@sciecure.com |
|
| Received: September 16, 2016 Accepted: October 04, 2016 Published: October 07, 2016 | |
| Citation: Baishya H, Yangxing Z, Wangshengmin, Hui LS (2016) The Influence of HPMC Viscosity and %HPC Content as FRC Parameter on the Release of Highly Soluble Drug from Hydrophilic Matrix Tablets. J Pharm Drug Deliv Res 5:6. doi: 10.4172/2325-9604.1000155 |
Abstract
A selective and sensitive liquid chromatography–mass spectrometry (AB SCIEX QTRAP 5500) method was developed for quantitative determination of genotoxic impurity, hexyl chloroformate, in drug substance. The method was developed by derivatizing the hexyl chloroformate (HCF) to complex compound hexyl benzylcarbamate (HBC) by reaction with benzylamine. This method provided good sensitivity for quantification of hexyl chloroformate at a concentration of 10 ppm in 10 mg/mL DEM sample solution. The compounds were chromatographed under isocratic condition on poroshell EC-C18 (2.7 μm particle packed in 4.6 x 50 mm column) column with mobile phase of 0.1% v/v ammonium hydroxide in water (pH adjusted to 6 using acetic acid) and acetonitrile in ratio of 1:1 v/v at the flow rate of 1.0 ml/minute with triple quadrupole Q-Trap 5500 mass spectrometer operated in multiple reaction monitoring mode (MRM). To produce transition ion of 236/152 the molecular mass of 236(M+H) was used as molecular ion. Positive mode electro spray ionization (ESI) was employed as the ionization source. The developed method was validated in terms of specificity, limit of detection (LOD), limit of quantification (LOQ), linearity, precision, accuracy, and robustness. The LOD & LOQ were found at 2.1 and 4.2 ppm, respectively.
Keywords: Functionality-related characteristics (FRC); Hydroxypropyl methylcellulose (HPMC); Apparent viscosity; Degree of substitution for Hydroxypropyl content; Dissolution testing
Keywords |
|
| Functionality-related characteristics (FRC); Hydroxypropyl methylcellulose (HPMC); Apparent viscosity; Degree of substitution for Hydroxypropyl content; Dissolution testing | |
Introduction |
|
| Apparent viscosity and degree of substitution for Hydroxypropyl content are functionality-related characteristics (FRC) of HPMC, when used as binder, film former, viscosity-increasing agent and especially as matrix former in Extended-release tablets [1,2]. The FRC of excipients are those physical and chemical characteristics, which have great impact on manufacturing and end-product performance. HPMC is described as a partly O-methylated and O-(2- hydroxypropylated) cellulose. It is available in several grades that vary in viscosity and degree of substitution [3]. HPMC is widely used as a drug release rate controlling excipient in hydrophilic matrix tablets, since it is odourless, tasteless, non-toxic and easy to handle [4,5]. The ratio and distribution of the methyl and Hydroxypropyl substitution as well as molecular weight of HPMC determine the final physicochemical properties and behaviour of HPMC [5,6]. It is important to stress that the parameters of viscosity and degree of substitution in specifications that determine the quality of specific HPMC grade are within relatively broad ranges. In the current formulation HPMC K15M and HPMC K100M are used in the formulation as rate controlling polymers. The viscosity specification range for HPMC K15M and HPMC K100M is 13275 – 24780 mPa.s and 75000 – 140000 mPa.s respectively. That of % HPC is 8.5 – 10.5% and 9.5 – 11.5% respectively for HPMC K15M and HPMC K100M. | |
| Our aim was to investigate the influence of apparent viscosity and %Hydroxypropyl content as functionality-related characteristic of HPMC K15M and HPMC K100M on the release of model drug from HPMC based hydrophilic matrix tablets. | |
Materials and Methods |
|
| Materials | |
| Niacin was procured from Divi’s Laboratories Limited, INDIA. HPMC 2208 - HPMC K15M & HPMC K100M (Colorcon), Povidone K90 (ISP Technologies), Stearic Acid (Shanghai Chineway). All Investigated HPMC samples are listed in Table 1. | |
 |
Table 1: Apparent viscosity and Hydroxypropyl content for evaluated samples of HPMC K15 and HPMC K100M. |
| Preparation of tablets by dry granulation method | |
| A factorial design (FFD) for two factors at two levels (22 factorial design [7,8]) was selected to screen the varied response variable. The two factors viz. HPMC K15M and HPMC K100M were varied with the QbD Samples and factor levels were coded (A for Low Viscosity, B for High Viscosity). Similarly 22 factorial design of experiments is applied to evaluate the effect of HMPC K15 M and HPMC K100M % Hydroxypropyl content QbD Samples and factor levels were coded (C for Low % HP and D for High % HP). | |
| A total of 8 feasibility trials are planned with similar quantitative composition with different QbD samples of HPMC K15M and HPMC K100 M. The Quantitative Tablet composition is as per Table 2. | |
|
Table 2: Different tablet compositions |
| Table 3, shows the factor combinations as per chosen experimental design. All the other materials are same as the Table 2. The grade of QbD samples differ and are tabulated in table below: Matrix tablets were prepared by wet granulation method the composition of various formulations is given in Table 2 and 3. | |
|
Table 3: QbD samples composition used in the present study. |
| Povidone K90, Niacin and Hypromellose K15M is sifted through sieve #40 mesh and blended in Rapid mixer granulator for 5 minutes. The blended material is granulated using purified water for suitable granules properties. The granules is dried in Fluid bed dryer and milled through comil fitted with suitable screen size. The milled granules is blended with extragranular material and lubricated with Stearic acid for 5 minutes and evaluated for the granular properties. Tablets were compressed on 19.18 × 8.25 mm capsule shaped punches on 10 station mini press tableting machine (Guoyao Longli). Eight different formulas having different concentrations of HPMC K4M were prepared. These tablets were evaluated for physical parameters and drug release profile to study the effect of apparent viscosity and % Hydroxypropyl content on drug release profile. | |
| Evaluation of Granules properties | |
| The lubricated granules were evaluated for granules parameter Viz., Bulk density, tapped density, compressibility index, and Hausner ratio and particle size distribution. Using routine lab model, the particle size distribution was conducted using Sieve shaker apparatus. | |
| Evaluation of tablets | |
| The prepared tablets were tested as per standard procedure for weight variation (n=10), hardness (n=10), thickness (n=10) and friability. Hardness of the tablets was determined by using Erweka tablet hardness tester, Friability test (n=10) was conducted using Roche friabilator (F. Hoffman-La Roche Ltd, Basel, Switzerland). Thickness of the tablets was measured by digital Vernier calipers (Aerospace). To study the effect of effect of apparent viscosity and % Hydroxypropyl content on drug release, the compressed tablets were evaluated for dissolution profile. Figure 1 shows the drug release profiles of the 6 formulations studied. | |
|
Figure 1: Effect of functionality related characteristics of HPMC K15M and HPMC K100M on compressibility index of various trial formulation. |
| Dissolution testing | |
| Dissolution studies were performed using the USP I, Basketrotating method (Electrolab dissolution tester, TDT-08, India) at 37°C ± 0.5°C and 100 rpm using water at 900 ml, as the dissolution media. A 2 ml aliquot of sample was withdrawn at regular time intervals, filtered and then these samples were diluted 10 folds with distilled water and then assayed using High performance liquid chromatography. The cumulative % drug release was calculated for the formulations. | |
| Data analysis using design of experiments | |
| For the studied design, the multiple linear regression analysis (MLRA) method was applied using the design Expert software to fit the full second order polynomial equation with added interaction terms. Compressibility index, particle size distribution and dissolution at different time point are considered as response factors for the study evaluation. ANOVA for the evaluated parameters and model significance were analysed. | |
Results and Discussion |
|
| Optimization of functionality related characteristic variables for development of Niacin ER tablets using 22 factorial design | |
| A 22 full factorial experimental design was implemented to prepare Niacin ER Tablets by Wet granulation method. Experimental design was used to optimize Functionality related characteristic of HPMC K15M and HPMC K100M viz. Viscosity and % Hydroxypropoxyl content. | |
| % compressibility Index, Particle size distribution and % drug release at 1 hour, 6 hour, 12 hour and 20 hour was selected as dependent variable | |
| Granules properties | |
| The lubricated granules were evaluated for granules parameter Viz., Bulk density, tapped density, compressibility index, and Hausner ratio and particle size distribution. The results are compiled in Table 4. The flow property indicated by empirical value of compressibility index shows that all the batches had satisfactory flow properties. Particle size distribution of lubricated granules is found to be similar for all the manufactured batches without any significant difference in Granulometry. Figures 1 and 2 shows Bar Diagram showing the relative effect of factors on response variable. Figures 1 and 2 shows the Pareto chart and contour plot for effect of apparent viscosity and % Hydroxypropyl content on % compressibility index and % particle size distribution of the formulation (Figure 3-5). The main effect of apparent viscosity and % hydroxypropoxyl content of HPMC K15M and HPMC K100M is less than the Bonferroni limit. Also contour plot indicates there are no interaction effect of apparent viscosity and % Hydroxypropyl content of HPMC K15M and HPMC K100M on % compressibility index and % particle size distribution of the formulation. This functionality-related characteristic of HPMC K15M and HPMC K100M is bound to have negligible effect on the granules properties. | |
|
Table 4: Granules properties of Formulations Prepared. |
|
Figure 2: Effect of functionality related characteristics of HPMC K15M and HPMC K100M on % Particle size distribution of various trial formulation. |
|
Figure 3: Pareto Chart and Contour plot for effect of apparent viscosity and Hydroxypropyl content on % compressibility index of the formulation. |
|
Figure 4: Pareto Chart and Contour plot for effect of apparent viscosity and Hydroxypropyl content on % particle size distribution of the formulation. |
|
Figure 5: Effect of functionality related characteristics of HPMC K15M and HPMC K100M on % Drug release profile of various trial formulation. |
| Physical properties | |
| The results obtained for the weight variation, hardness, thickness and friability are given in Table 5. All the prepared formulations were seen to be complying with the predetermined specification criteria. The hardness and friability, the measures of strength of the tablets were found to be >150 N and <1% respectively, these values were within limit. Thus all the physical parameters of the compressed matrices were found to be practically within controls. | |
|
Table 5: Table Physical properties of Formulations Prepared. |
| In-vitro dissolution study | |
| Figure 6 shows the Pareto chart and contour plot for effect of apparent viscosity and % Hydroxypropyl content on % drug release of the formulation. The main effect of apparent viscosity and % hydroxypropoxyl content of HPMC K15M and HPMC K100M is less than the Bonferroni limit. Also contour plot indicates there are no interaction effect of apparent viscosity and % Hydroxypropyl content of HPMC K15M and HPMC K100M on % drug release at different dissolution time point of the formulation. | |
|
Figure 6: Pareto Chart and Contour plot for effect of apparent viscosity and Hydroxypropyl content on % drug release profile of the formulation. |
Conclusion |
|
| In the present study critical material attributes of HPMC K15M and HPMC K100M (Apparent viscosity and % HP content) and their impact on hydrophilic matrix tablets were evaluated for on Niacin ER Tablets formulation. According to this study granules parameter and in vitro dissolution was considered as the critical quality attributes for the trial formulation. Hence, this CQA was evaluated using 22 full factorial designs. Design expert (version 9.0) was used for statistical evaluation of the QbD samples of HPMC K15M and HPMC K100M. All prepared batches Trial 1 to Trial 8 were evaluated for Critical quality attributes. This study shows that apparent viscosity and % Hydroxypropoxyl content variation, within the manufacturer’s specifications for HPMC K15M and HPMC K100M grades, has minimal impact on CQA for Niacin ER Tablets. These results highlight the consistency of the HPMC K15M and HPMC K100M product and utility of Hypromellose QbD samples as a means to develop robust modified release dosage forms. Hence, it was not required to postulate specification limits for viscosity and % HPC during the development stage. | |
Acknowledgment |
|
| We are extremely gratified to Formulation development Department and fellow colleagues of Beijing Sciecure Pharmaceuticals Co., Ltd.,, for helping us in the technical aspect of the project and also for useful scientific discussions, which produced methodical results and also for sharing their passion for drug product development and thus helping us in better understanding of critical process and quality attributes for drug development. | |
References |
|
|
|
