Eudragit(®) RS PO/RL PO as rate-controlling matrix-formers via roller compaction: Influence of formulation and process variables on functional attributes of granules and tablets.

The influence of plasticizer level, roll pressure and sintering temperature was investigated on the granule properties, tablet breaking force and theophylline release from tablets. Nine formulations using theophylline as a model drug, Eudragit(®) RL PO, Eudragit(®) RS PO, or both as a matrix former and triethyl citrate (TEC) as a plasticizer were prepared. The formulations were roller compacted and the granules obtained were evaluated for particle size distribution and flowability. These granules were compacted into tablets at a compression force of 7 kN. The tablets were thermally treated at different temperatures (50 and 75°C) for 5 h and were evaluated for breaking force and dissolution. Increase in roll pressure and TEC levels resulted in a progressive increase in the mean particle size of the granules. The flowability of the granules also improved with increasing roll pressures and TEC levels. Tablet breaking force increased with an increase in TEC levels and sintering temperatures. But these effects were significant only at the highest level of plasticizer and sintering temperature respectively. For the tablets containing Eudragit(®) RS PO, theophylline release decreased proportionately with increase in TEC levels and sintering temperatures. Tablets containing either Eudragit(®) RL PO or a mixture of RS PO and RL PO failed to impart an extended-release property to the tablets at the studied variables i.e. roll pressure, TEC levels and sintering temperature. It was clearly demonstrated that with suitable optimization of these parameters, the release-rate of a water soluble drug from the matrix tablets prepared via roller compaction can be finely controlled.

Quality by design, part II: application of NIR spectroscopy to monitor the coating process for a pharmaceutical sustained release product.

Ammonio methacrylate copolymers are commercially available as Eudragit RL/RS; they differ in the degree of quaternary ammonium group substitution, which gives them different permeabilities. These closely related polymers can be combined in various ratios to control release rate; consequently, release rate is controlled by the polymer composition and coating thickness. Therefore, predicting drug release from methacrylate copolymers using near infrared spectroscopy (NIRS) can be technically difficult. Thus, the objective of this study is to use NIRS to develop multivariate calibration models to predict tablet coat thickness and release rate for tablets coated with varying polymer ratios. A series of sustained release orbifloxacin formulations were developed with varying polymer ratios. Partial least squares (PLS) models were developed to predict coat thickness; samples from these formulations were pooled and a combined calibration was generated. To assess dissolution, tablets were coated using Eudragit RL and RS with ratios of 0:5, 1:4, 2:3, 3:2, 4:1, and 5:0. The amount released at set time-points was used to build PLS models. For the first time, NIRS has been successfully used to monitor Eudragit polymer coat thickness and drug release from tablets coated with various RL:RS ratios, which demonstrates the potential of NIRS as tool for coating process.

Quality by design, part III: study of curing process of sustained release coated products using NIR spectroscopy.

This study investigated the potential of near infrared spectroscopy (NIRS) to assess film coat curing for tablets coated with methacrylate copolymers. The ability of NIRS to monitor film coat curing was studied and compared to conventional methods like differential scanning calorimetry (DSC) and hot-stage microscopy (HSOM). This study showed that variation in the curing temperature and duration affected the NIR spectra for all formulations. These results and the DSC and HSOM results showed that the spectral changes are due to polymer curing. In addition, glass beads, theophylline and orbifloxacin tablets were coated using Eudragit RL, RS, and L 30-D with varying ratios. Principal component analysis (PCA) was performed on the NIR spectra to investigate the effect of curing time and temperature on cast films, uncoated tablets, coated tablets and coated glass beads. Score plots showed that curing duration and temperature affected coated glass beads, uncoated and coated tablets significantly. The amount of drug released at 250 min, and the NIR spectra of cured tablets were used to develop and validate a 7-factor partial least square (PLS) regression calibration for theophylline tablets coated with Eudragit RL:RS 30-D (1:4). This study demonstrated the potential of NIRS in film coat curing and release monitoring.

Quality by design, part I: application of NIR spectroscopy to monitor tablet manufacturing process.

To monitor tableting production using near infrared (NIR) spectroscopy, chemometric models were developed to analyze peak compression force, crushing strength and content uniformity. To measure tablet content uniformity, orbifloxacin tablets with drug content ranging from 60 to 90 mg were made and analyzed using ultraviolet (UV) and NIR spectroscopy. To assess the compression force and crushing strength, several batches of tablets were made on a Stokes B2 rotary tablet press and compression force was varied from 360 to 3500 lb. Principal component analysis (PCA) was used to identify tablets with regular and capped tablets breakage patterns. Comparison of statistical parameters showed that partial least squares (PLS) models gave better fit than the multiple linear regression (MLR) models. The best fit PLS models had a standard error of calibration (SEC) and a standard error of prediction (SEP) for content uniformity of 1.13 and 1.36 mg; for compression force of 69.86 and 59.48 lb and for crushing strength 0.55 kP and 0.57 kP, respectively. NIR spectroscopy in combination with multivariate modeling is a rapid and nondestructive technique that could reliably predict content uniformity, compression force and crushing strength for orbifloxacin tablets.

Assessment of NIR spectroscopy for nondestructive analysis of physical and chemical attributes of sulfamethazine bolus dosage forms.

The goal of this study was to assess the utility of near infrared (NIR) spectroscopy for the determination of content uniformity, tablet crushing strength (tablet hardness), and dissolution rate in sulfamethazine veterinary bolus dosage forms. A formulation containing sulfamethazine, corn starch, and magnesium stearate was employed. The formulations were wet granulated with a 10% (wt/vol) starch paste in a high shear granulator and dried at 60 degrees C in a convection tray dryer. The tablets were compressed on a Stokes B2 rotary tablet press running at 30 rpm. Each sample was scanned in reflectance mode in the wavelengths of the NIR region. Principal component analysis (PCA) of the NIR tablet spectra and the neat raw materials indicated that the scores of the first 2 principal components were highly correlated with the chemical and physical attributes. Based on the PCA model, the significant wavelengths for sulfamethazine are 1514, (1660-1694), 2000, 2050, 2150, 2175, 2225, and 2275 nm; for corn starch are 1974, 2100, and 2325 nm; and for magnesium stearate are 2325 and 2375 nm. In addition, the loadings show large negative peaks around the water band regions ( approximately 1420 and 1940 nm), indicating that the partial least squares (PLS) models could be affected by product water content. A simple linear regression model was able to predict content uniformity with a correlation coefficient of 0.986 at 1656 nm; the use of a PLS regression model, with 3 factors, had an r (2) of 0.9496 and a standard error of calibration of 0.0316. The PLS validation set had an r (2) of 0.9662 and a standard error of 0.0354. PLS calibration models, based on tablet absorbance data, could successfully predict tablet crushing strength and dissolution in spite of varying active pharmaceutical ingredient (API) levels. Prediction plots based on these PLS models yielded correlation coefficients of 0.84 and 0.92 on independent validation sets for crushing strength and Q(120) (percentage dissolved in 120 minutes), respectively.

Dissolution test development for complex veterinary dosage forms: oral boluses.

Fundamental aspects of electrolyte chemistry were used to design an appropriate dissolution medium with the capacity to maintain sink conditions throughout the test. Dissolution of various bolus dosage forms was studied using USP Apparatus II at various stirring speeds. Complete dissolution of each drug in the designed medium was achieved, and there is evidence that such a dissolution test could be discriminating. This review details the development of potentially discriminating in vitro dissolution tests for veterinary boluses using USP Apparatus II and examines the potential role of such testing during product quality assessments, in the evaluation of postapproval manufacturing changes and for the establishment of the generic equivalence of veterinary products.