Using an experimental design to identify and quantify the effects of environment related test parameters on the in vitro mucoadhesivity testing of a propanolol buccal tablet

This study sought to identify and quantify the effects of environmental test parameters on the mucoadhesivity of a propranolol tablet. Their effects on Maximum Detachment Force (MDF) measurements were evaluated using a Box-Behnken design matrix. Prehydration time (PT) had a statistically significant negative main effect while contact force (CF) had no significant effect on in vitro MDF measurements. While contact time (CT) had no significant main or quadratic effects, it had a positive interaction effect with PT. The mathematical model was statistically validated and a PT of 3.5 min and a CT of 5 min was proposed for mucoadhesion testing by the tensile method during formulation optimization.     

Power of Experimental Design Studies for the Validation of Pharmaceutical Processes: Case Study of a Multilayer Tablet Manufacturing Process

ABSTRACT

Experimental design studies (EDS) are already widely used in the pharmaceutical industry for drug formulation or process optimization. Rare are the situations in which this methodology is applied for validation purposes. The power of this statistical tool, key element of a global validation strategy, is demonstrated for a multilayer tablet manufacturing process. Applied to the Geomatrix® system generally composed of one compression and three granulation processes, time and strictness gains are non-negligible. Experimental design studies are not used in this work for modeling. Introduced at each important step of the process development, they allow for the evaluation of process ruggedness at pilot scale and specifications for full production. A demonstration of the complete control of key process parameters is given, identified throughout preliminary studies.     

Using Experimental Design to Optimize the Process Parameters in Fluidized Bed Granulation

In this study many parameters were screened for a small-scale granulation process for their effect on the yield of granules between 75 and 500 μm and the geometrical granule mean size (d50). First a Plackett-Burman design was applied to screen the inlet air temperature, the inlet flow rate, the spray rate, the nozzle air pressure, the nozzle spray diameter, and the nozzle position. The Plackett-Burman design showed that the key process parameters were the inlet flow rate and the spray rate and probably also the inlet air temperature. Afterward a fractional factorial design (2^5?2) was applied to screen the remaining parameters plus the nozzle aircap position and the spraying time interval. The fractional factorial design showed that the nozzle air pressure was also important. As the target values for the granule yield (between 75 and 500 μm) and the geometric mean granule size (between 300 and 500 μm) were reached during the screening experiments, further optimization was not considered necessary.     

Formulation Design of an HPMC-Based Sustained Release Tablet for Pyridostigmine Bromide as a Highly Hygroscopic Model Drug and its In Vivo/In Vitro Dissolution Properties

Pyridostigmine bromide (PB), a highly hygroscopic drug was selected as the model drug. A sustained-release (SR) tablet prepared by direct compression of wet-extruded and spheronized core pellets with HPMC excipients and exhibited a zero-order sustained release (SR) profile. The 2³ full factorial design was utilized to search an optimal SR tablet formulation. This optimal formulation was followed zero-order mechanism and had specific release rate at different time intervals (released % of 1, 6, and 12 hr were 15.84, 58.56, and 93.10%). The results of moisture absorption by Karl Fischer meter showed the optimum SR tablet could improve the hygroscopic defect of the pure drug (PB). In the in vivo study, the results of the bioavailability data showed the T_max was prolonged (from 0.65 ± 0.082 hr to 4.83 ± 1.60 hr) and AUC_0–t (from 734.88 ± 230.68 ng/ml.hr to 1153.34 ± 488.08 ng/ml.hr) and was increased respectively for optimum PB-SR tablets when compared with commercial immediate release (IR) tablets. Furthermore, the percentages of in vitro dissolution and in vivo absorption in the rabbits have good correlation. We believe that PB-SR tablets designed in our study would improve defects of PB, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo for personnel exposed to contamination situations in war or terrorist attacks in the future.     

Preparation and In Vitro Evaluation of Controlled Release Hydrophilic Matrix Tablets of Ketorolac Tromethamine Using Factorial Design

Controlled release matrix tablets of ketorolac tromethamine (KT) were prepared by direct compression technique using cellulose derivatives as hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), and carboxymethyl cellulose (CMC) in different concentrations (10–20%). The effect of polymer type and concentration was investigated on drug release by 2³ factorial design. For the quality control of matrix tablets, weight deviation, hardness, friability, diameter–height ratio, content uniformity of KT, and in vitro dissolution technique were performed. UV Spectrophotometric method was used to detection of KT in matrix tablets. This method was validated. Dissolution profiles of the formulations were plotted and evaluated kinetically. An increase in polymer content resulted with a slow release rate of drug as was expected. According to the dissolution results, tablets prepared with HPMC + HEC + CMC (F1 and F8) were found to be the most suitable formulation for KT. About 99.27% KT was released from F8 in 7 h.     

Influence of Hydroxypropyl Methylcellulose Mixture,Apparent Viscosity,and Tablet Hardness on Drug Release Using a 23 Full Factorial Design

ABSTRACT

This study investigates the effects of three factors: (1) use of a mixture of two different grades of hydroxypropyl methylcellulose (HPMC), (2) apparent viscosity, and (3) tablet hardness on drug release profiles of extended-release matrix tablets. The lot-to-lot apparent viscosity difference of HPMC K15M on in vitro dissolution was also investigated. Four test formulations were made, each containing 10% of a very water-soluble active pharmaceutical ingredient (API), 32% HPMC K15M, or a mixture of HPMC K100LV and HPMC K100M, 56% diluents, and 2% lubricants. Each formulation was made at two hardness levels. A 2³ full factorial design was used to study various combinations of the three factors using eight experiments conducted in a randomized order. Dissolution studies were performed in USP apparatus I. The values of t_50% (time in which 50% drug is released) and t_lag (lag time, the time taken by the matrix tablet edges to get hydrated and achieve a state of quasi-equilibrium before erosion and the advance of solvent front through the matrix occur) were calculated from each dissolution profile. The similarity factor (f₂) was also calculated for each dissolution profile against the target dissolution profile. A simple Higuchi-type equation was used to analyze the drug release profiles. Statistical analysis using analysis of variance (ANOVA) and similarity factor (f₂) values calculated from the data indicated no significant difference among the t_50% values and dissolution profiles respectively for all formulations. Within the 3.3–6 kp hardness range investigated, dissolution rates were found to be independent of tablet hardness for all the formulations. Although significantly shorter lag times were observed for the tablets formulated with low- and high-viscosity HPMC mixtures in comparison to those containing a single grade of HPMC, this change had no significant impact on the overall dissolution profiles indicated by the similarity factor f₂ values. From this study it can be concluded that lot-to-lot variability in apparent viscosity of HPMC should not be a concern in achieving similar dissolution profiles. Also, results indicated that within the viscosity range studied (12,000–19,500 cps) an HPMC mixture of two viscosity grades can be substituted for another HPMC grade if the apparent viscosity is comparable. Also, the drug release is diffusion-controlled and depends mostly on the viscosity of the gel layer formed.