Nomogram for computing the value of similarity factor.

The objective of present work was to construct nomogram for obtaining a value of similarity factor (f2) by employing the values of number of observations (n) and sum of squared difference of percentage drug dissolved between reference (R) and test (T) products . The steps for rearrangement of equation of similarity factor are presented. The values of f2 were selected in the range of 45 to 100 for 4 to 12 observations (n) for computing the values of Linear regression analysis was performed between number of observations and . Perfect correlation was observed in each case. Nomogram was constructed and later it was validated by using drug dissolution data from literature and our laboratory. The use of nomogram is recommended during research and development work to investigate effect of formulation or process variables. The nomogram can also be used during change in manufacturing site or change in equipment. It is concluded that the steps for calculation of f2 can be truncated in the middle (i.e. at the step of calculation of factor and a decision of similarity/dissimilarity can be taken employing the nomogram.

Exploration of Novel Co-processed Multifunctional Diluent for the Development of Tablet Dosage Form.

The aim of this investigation was to develop a novel multifunctional co-processed diluent consisting of microcrystalline cellulose (Avicel PH 102), crospovidone (Polyplasdone XL) and polyethylene glycol 4000. Colloidal silicon dioxide and talc were also incorporated as minor components in the diluent to improve tableting properties. Melt granulation was adopted for preparation of co-processed diluent. Percentage of Avicel PH 102, Polyplasdone XL and polyethylene glycol 4000 were selected as independent variables and disintegration time was chosen as a dependent variable in simplex lattice design. The co-processed diluent was characterised for angle of repose, bulk density, tapped density, Carr's index, percentage of fines and dilution potential study. Acetaminophen and metformin were used as poorly compressible model drugs for preparation of tablets. The blend of granules of drug and extra-granular co-processed diluent exhibited better flow as compared to the blend of drug granules and physical mixture of diluents blend. The diluent exhibited satisfactory tableting properties. The tablets exhibited fairly rapid drug release. In conclusion, melt granulation is proposed as a method of preparing co-processed diluent. The concept can be used to bypass patents on excipient manufacturing.

Fabrication and Evaluation of Bi-layer Tablet Containing Conventional Paracetamol and Modified Release Diclofenac Sodium.

The objectives of present investigation were to achieve immediate release of paracetamol and tailored release of diclofenac sodium from bi-layer tablets. A 2(3) full factorial design was adopted using the amount of polyethylene glycol, microcrystalline cellulose and crospovidone as independent variables for fabricating paracetamol tablets. Diclofenac sodium tablets were prepared using hydroxypropyl methylcellulose as a matrixing agent. The results of analysis of variance showed that the friability of paracetamol was distinctly influenced by the formulation variables. The in vitro drug release behaviour of diclofenac tablets was compared with a marketed formulation. The optimized formulations of paracetamol and diclofenac sodium were used for manufacturing of bi-layer tablets. The bi-layer tablets showed immediate release of paracetamol and modified release of diclofenac.

Resolving issues of content uniformity and low permeability using eutectic blend of camphor and menthol.

The aim of present study were to arrest the problem of content uniformity without the use of harmful organic solvent and to improve ex vivo permeability of captopril, a low dose class III drug as per biological classification system. Eutectic mixture of camphor and menthol was innovatively used in the work. Captopril solution in eutectic mixture was blended with Avicel PH 102 and then the mixture was blended with mannitol in different ratios. Formulated batches were characterized for angle of repose and Carr's index. A selected batch was filled in hard gelatin capsule. Tablet dosage form was also developed. Capsules and tablets were characterized for in vitro drug release in 0.1N HCl. Additionally, the captopril tablets were analyzed for content uniformity and ex vivo drug permeation study using rat ileum in modified apparatus. The measurement of angle of repose and Carr's index revealed that the powder blend exhibited good flow property and compressibility. The captopril capsules and tablets exhibited immediate drug release in 0.1 N HCl. The captopril tablets passed content uniformity test as per IP 1996. Ex vivo permeation of captopril, formulated with eutectic mixture, was faster than control. The permeation was increased by 15% at the end of 3 h. Tablets and capsule exhibited reasonable short term stability with no considerable change in performance characteristics.

Preparation and evaluation of soft gellan gum gel containing paracetamol.

The objective of this study was to develop soft paracetamol gel using gellan gum as a gelling agent and sodium citrate as a source of cation. Different batches were prepared using three different concentrations of gellan gum (0.1, 0.3, and 0.5%), each with two different sodium citrate concentrations (0.3 and 0.5%). The consistency of the paracetamol gel was dependent on the concentration of gellan gum, sodium citrate and co-solute. The results of dissolution study of soft gel containing 0.3% gellan gum and 0.3% sodium citrate revealed that paracetamol was completely released in 30 min. Polyethylene glycol 400 worked as a solubilizer for paracetamol. All the gels possessed acceptable sensory characteristics when evaluated by human volunteers. Short term stability study carried out for four weeks at different temperatures revealed no considerable changes in performance characteristics of developed optimized formulation.

Mathematical approach for the assessment of similarity factor using a new scheme for calculating weight.

The objective of the present work was to propose a method for calculating weight in the Moore and Flanner Equation. The percentage coefficient of variation in reference and test formulations at each time point was considered for calculating weight. The literature reported data are used to demonstrate applicability of the method. The advantages and applications of new approach are narrated. The results show a drop in the value of similarity factor as compared to the approach proposed in earlier work. The scientists who need high accuracy in calculation may use this approach.

Exploration of cold extrusion for the preparation of enteric minitablets of isoniazid.

The objective of the present work was to formulate the enteric minitablets of isoniazid by cold extrusion method. The minitablets were prepared using isoniazid, hydroxylpropylmethylcellulose phthalate and dibasic calcium phosphate. The minitablets were coated using hydroxypropylmethylcellulose phthalate. Full factorial design was adopted to optimize the formulation. The minitablets showed good flow and acceptable friability. The drug release was resisted in 0.1 N HCl for 2 h from the optimized batch. The optimized batch showed more than 90% of drug release in phosphate buffer in 15 min. Capsules containing rifampicin powder and enteric isoniazid minitablets showed complete drug release in acidic and alkaline media respectively. The process of cold extrusion appears to be an attractive alternative to by-pass the existing patents.

Modulation of venlafaxine hydrochloride release from press coated matrix tablet.

The aim of present study was to prepare novel modified release press coated tablets of venlafaxine hydrochloride. Hydroxypropylmethylcellulose K4M and hydroxypropylmethylcellulose K100M were used as release modifier in core and coat, respectively. A 3(2) full factorial design was adopted in the optimization study. The drug to polymer ratio in core and coat were chosen as independent variables. The drug release in the first hour and drug release rate between 1 and 12 h were chosen as dependent variables. The tablets were characterized for dimension analysis, crushing strength, friability and in vitro drug release. A check point batch, containing 1:2.6 and 1:5.4 drug to polymer in core and coat respectively, was prepared. The tablets of check point batch were subjected to in vitro drug release in dissolution media with pH 5, 7.2 and distilled water. The kinetics of drug release was best explained by Korsmeyer and Peppas model (anomalous non-Fickian diffusion). The systematic formulation approach enabled us to develop modified release venlafaxine hydrochloride tablets.

A review of co-processed directly compressible excipients.

Direct compression is the preferred method for the preparation of tablets. The present review outlines the importance of the functionality of the directly compressible adjuvants in the formulation of tablets. The co-processing is the most widely explored method for the preparation of directly compressible adjuvants because it is cost effective and can be prepared in-house based on the functionality required. Hence, the present review focuses on the properties of the co-processed directly compressible adjuvants available in the market.

Development of modified release diltiazem HCl tablets using composite index to identify optimal formulation.

This article reports the preparation of tartaric acid treated ispaghula husk powder for the development of modified release tablets of diltiazem HCl by adopting direct compression technique and a 32 full factorial design. The modified ispaghula husk powder showed superior swelling and gelling as compared to untreated powder. Addition of compaction augmenting agent such as dicalcium phosphate was found to be essential for obtaining tablets with adequate crushing strength. In order to improve the crushing strength of diltiazem HCl tablets, to modulate drug release pattern, and to obtain similarity of dissolution profiles in distilled water and simulated gastric fluid (pH 1.2), modified guar gum was used along with modified ispaghula husk powder and tartaric acid. A novel composite index, which considers a positive or a negative deviation from an ideal value, was calculated considering percentage drug release in 60, 300, and 540 min as dependent variables for the selection of a most appropriate batch. Polynomial equation and contour plots are presented. The concept of similarity factor (f2) was used to prove similarity of dissolution in water and simulated gastric fluid (pH 1.2).

Processing of nimesulide-PEG 400-PG-PVP solid dispersions: preparation, characterization, and in vitro dissolution.

The objective of this investigation was to study the influence of dissolution enhancers such as polyethylene glycol 400, propylene glycol, polyvinylpyrrolidone K30, sodium lauryl sulfate, and Tween 80 on in vitro dissolution of a model active pharmaceutical material--nimesulide. Preliminary studies were conducted using a physical blend of nimesulide, and the adjuvants and solid dispersions were prepared using solvent evaporation and cogrinding methods. Aqueous solution of adjuvants was first triturated with nimesulide, followed by mixing with lactose and microcrystalline cellulose, and finally water was evaporated under vacuum in a cogrinding method. A 33 factorial design was adopted in a cogrinding method using the concentration of polyethylene glycol 400, propylene glycol, and polyvinylpyrrolidone K30 as independent variables. Tween 80 and sodium lauryl sulfate were added in all the batches. Full and reduced models were evolved for different dependent variables. The reduced models were validated using two checkpoints. Angle of repose < 35 degrees, percentage of drug released in 30 min (Q30) > 40%, 45 min (Q45) > 50%, and 120 min (Q12) > 60% were used as constraints for the selection of an optimized batch. Contour plots are presented for the selected dependent variables. Polyvinylpyrrolidone was found to be more effective in increasing the drug dissolution, compared with polyethylene glycol 400 and propylene glycol. The granule flow was adversely affected when high levels of liquid adjuvants were used in formulations. Wettability study was conducted to measure wetting time for pure drug and the optimized batch. Improved drug dissolution was attributed to improved wetting and the solubilizing effect of adjuvants from the pseudosolid dispersions of nimesulide. Significant improvement in drug dissolution was observed (Q120 = 70%), compared with pure drug powder (Q120 = 15%). In conclusion, dissolution of nimesulide can be modulated using an appropriate blend of pharmaceutical adjuvants.

Studies in release behavior of diltiazem HCl from matrix tablets containing (hydroxypropyl)methyl cellulose and xanthan gum.

(Hydroxypropyl)methyl cellulose and xanthan gum were used as hydrophilic matrixing agents for preparing modified release tablets of diltiazem HCl. The amount of (Hydroxypropyl)methyl cellulose and xanthan gum exhibited significant effect on drug release from the tablets prepared by direct compression technique. Xanthan gum showed a higher ability to retard the drug release than (Hydroxypropyl)methyl cellulose. A 2(2) + 1 factorial design was adopted to study the effect of amount of (Hydroxypropyl)methyl cellulose and xanthan gum on percent drug released in first hour (Y60) and the time required for 90% drug dissolution (t90). A response surface plot is generated for investigating the effect of the independent variables on t90. The tablets containing 90 mg diltiazem HCl, 45 mg (Hydroxypropyl)methyl cellulose and 45 mg xanthan gum showed drug release upto 12 h. The value of similarity factor, f2, for the selected batch was found to be 85.1 when the dissolution study was carried out in water or simulated gastric fluid, indicating pH independent drug dissolution. The selected batch also showed a comparable release profile with a market product (f2 = 60.2). Linear relationship was observed between percent drug released and degree of swelling. The kinetics of the drug release fitted well to the Hixson-Crowell equation. It can be concluded that by using a suitable blend of (Hydroxypropyl)methyl cellulose and xanthan gum desired modified drug release can be achieved.

Novel use of similarity factors f2 and Sd for the development of diltiazem HCl modified-release tablets using a 3(2) factorial design.

The objective of this study was to develop modified-release tablets of diltiazem HCl using a direct compression technique. A 3(2) factorial design was employed using the amount of alkali-treated guar gum and cetyl alcohol as independent variables. This article proposes the use of a novel approach-f2 and Sd values as dependent variables-to evaluate the effect of selected independent variables along with other dependent variables (i.e., percentage drug released in x min, Yx; time required for z% drug release, tz; and mean dissolution time (MDT)). It is concluded that when a decision is to be made for the selection of a best batch, it is perhaps more realistic to use the f2 or Sd value which takes into account the dissolution profile as a whole, as opposed to Yx and tz values which use just one point from the dissolution plot. The batch showing the f2 value nearest to 100 or the Sd value nearest to zero is ranked as the best batch (diltiazem HCl 90 mg, alkali-treated guar gum 80 mg and cetyl alcohol 15 mg). The gel strength and matrix erosion of the formulated tablets were dependent on the type and amount of the adjuvants. The drug release rate is well correlated with matrix erosion. The kinetics of drug release fitted best to the Korsmeyer and Peppas model. It is concluded that by using a proper combination of the hydrophilic polymer and cetyl alcohol one can achieve a desirable drug release pattern.

Modulation of drug release rate of diltiazem-HCl from hydrogel matrices of succinic acid-treated ispaghula husk.

The feasibility of using succinic acid-treated ispaghula husk in matrix-based tablets of diltiazem-HCl was investigated. The sample prepared using 4:1 weight ratio of ispaghula husk to succinic acid showed improved swelling and gelling. A 3(2) factorial design was employed to investigate the effect of amount of succinic acid-treated ispaghula husk and dicalcium phosphate (DCP) on the percentage of the drug dissolved in 60, 300, and 480 min from the compressed tablets. The results of multiple linear regression analysis revealed that the significance of the amount of succinic acid-treated ispaghula husk was greater in magnitude than that of the amount of DCP in controlling the drug release. Acceptable batches were identified from a contour plot with constraints on the percentage drug released at the three sampling times. A mathematical model was also evolved to describe the entire dissolution profile. The results of F-test revealed that the Higuchi model fits well to the in vitro dissolution data. The tablets showed considerable radial and axial swelling in distilled water. Succinic acid-treated ispaghula husk can be used as an economical hydrophilic matrixing agent.

Novel mathematical method for quantitative expression of deviation from the higuchi model.

A simple mathematical method to express the deviation in release profile of a test product following Higuchi's kinetics from an ideal Higuchi release profile was developed. The method is based on calculation of area under the curve (AUC) by using the trapezoidal rule. The precision of prediction depends on the number of data points. The method is exemplified for 2 dosage forms (tablets of diltiazem HCl and microspheres of diclofenac sodium) that are designed to release the drug over a 12-hour period. The method can be adopted for the formulations where drug release is incomplete (<100%) or complete (100%) at last sampling time. To describe the kinetics of drug release from the test formulation, zero-order, first-order, Higuchi's, Hixson-Crowell's, and Weibull's models were used. The criterion for selecting the most appropriate model was based on the goodness-of-fit test. The release kinetics of the tablets and microspheres were explained by the Higuchi model. The release profiles of the test batches were slightly below the ideal Higuchi release profile. For the test products, observed percentage deviation from an ideal Higuchi profile is less than 16% for tablets and less than 11% for microspheres. The proposed method can be extended to the modified release formulations that are designed to release a drug over 6, 18, or 24 hours. If the data points are not evenly separated, the ideal drug release profile and AUC are calculated according to the specific sampling time. The proposed method may be used for comparing formulated products during the research and development stage, for quality control of the products, or for promoting products by comparing performance of the test product with that of the innovator's product.

Formulation design and optimization of modified-release microspheres of diclofenac sodium.

The present study deals with the preparation of microspheres of diclofenac sodium using cross-linked poly(vinyl alcohol) (PVA). A central composite design consisting of a two-level full factorial design superimposed on a star design was employed for developing the microspheres. The PVA to the drug ratio X1 and amount of glutaral-dehyde cross-linking agent X2 were chosen as the independent variables. The time required for 50% drug dissolution t50 in phosphate buffer (pH 7.2) was selected as the dependent variable. An optimum polynomial equation was generated for the prediction of the response variable t50. Based on the results of multiple linear regression analysis and F statistics, it may be concluded that sustained action can be obtained when X1 and X2 are kept at high levels. The X1X2 interaction was found to be statistically significant. A response surface plot is presented to show the effects of X1 and X2 on t50. The drug release pattern fit the Higuchi model well. A model was validated for accurate prediction of the drug dissolution profile with constraints on the percentage drug release in the first, fifth, and seventh hours. The data of a selected batch were subjected to an optimization study, and an optimal formulation was fabricated. Good agreement was observed between the predicted and the observed dissolution profiles of the optimal formulation.

Preliminary investigations in matrix-based tablet formulations of diltiazem hydrochloride containing succinic acid-treated methylcellulose.

The feasibility of using succinic acid-treated methylcellulose in matrix-based tablets of diltiazem hydrochloride was investigated in this study. A 2(3) factorial design was employed to investigate the effect of ratio of methylcellulose to succinic acid, amount of ethyl alcohol, and drying time on the percentage drug dissolved in 300 min. The tablets were prepared by wet granulation technique. The ratio of methylcellulose to succinic acid was found to significantly influence the swelling and gelling characteristics of the polymer. Carbonyl peak was found in the infrared (IR) spectra of the samples modified using succinic acid, suggesting the presence of an ester group. The results of an ANOVA test revealed that the significance of the ratio of methylcellulose to succinic acid and drying time was greater in magnitude than that of amount of alcohol in controlling the drug release in 300 min. The results of F-test revealed that the zero-order model fits well to the in vitro dissolution data. The characteristics of methylcellulose can be changed by reacting it with succinic acid and the resultant product can be used as a hydrophilic matrixing agent.

Formulation optimization of controlled release diclofenac sodium microspheres using factorial design.

Diclofenac sodium is an ideal candidate for incorporation in a controlled release device to diminish its adverse effects after oral administration. Microspheres were prepared by using sodium alginate as a polymer and CaCl2 as a cross-linking agent. In this investigation, 3(3) full factorial design was used to investigate the joint influence of the three variables: the stirring speed (X1), concentration of CaCl2 (X2) and % of heavy liquid paraffin in a blend of heavy and light liquid paraffin in the dispersion medium (X3) on the time of 80% drug dissolution (t80). Potential variables such as concentration of sodium alginate and drug: sodium alginate ratio were kept constant in the experimental design. A statistical model with significant interaction terms is derived to predict t80. The results of multiple linear regression analysis and F-statistics revealed that for obtaining controlled drug release, the microspheres should be prepared using relatively lower stirring speed, higher concentration of CaCl2 and higher percentage of heavy liquid paraffin in the dispersion medium. The X1X2 and X2X3 interactions were found to be statistically significant in nature. A response surface plot is presented to show the effects of X1, X2 and X3 on t80. The drug was released by diffusion of anomalous type. A model was validated for accurate prediction of drug release profile. Acceptable batches were identified in the experimental design with constraints on percentage drug released in 1, 6 and 8 h.