Use of FT-NIR transmission spectroscopy for the quantitative analysis of an active ingredient in a translucent pharmaceutical topical gel formulation.

The objective of this study was to demonstrate the use of transmission Fourier transform near-infrared (FT-NIR) spectroscopy for quantitative analysis of an active ingredient in a translucent gel formulation. Gels were prepared using Carbopol 980 with 0%, 1%, 2%, 4%, 6%, and 8% ketoprofen and analyzed with an FT-NIR spectrophotometer operated in the transmission mode. The correlation coefficient of the calibration was 0.9996, and the root mean squared error of calibration was 0.0775%. The percent relative standard deviation for multiple measurements was 0.10%. The results prove that FT-NIR can be a good alternative to other, more time-consuming means of analysis for these types of formulations.

Prediction of drug content and hardness of intact tablets using artificial neural network and near-infrared spectroscopy.

The purpose of this study was to predict drug content and hardness of intact tablets using artificial neural networks (ANN) and near-infrared spectroscopy (NIRS). Tablets for the drug content study were compressed from mixtures of Avicel PH-101, 0.5% magnesium stearate, and varying concentrations (0%, 1%, 2%, 5%, 10%, 20%, and 40% w/w) of theophylline. Tablets for the hardness study were compressed from mixtures of Avicel PH-101 and 0.5% magnesium stearate at varying compression forces ranging from 0.4 to 1 ton. An Intact Analyzer was used to obtain near infrared spectra from the tablets with varying drug contents, whereas a Rapid Content Analyzer (RCA) was used to obtain spectral data from the tablets with varying hardness. Two sets of tablets from each batch (i.e., tablets with varying drug content and hardness) were randomly selected. One set of tablets was used to generate appropriate calibration models, while the other set was used as the unknown (test) set. A total of 10 ANN calibration models (5 each with 10 and 160 inputs at appropriate wavelengths) and five separate 4-factor partial least squares (PLS) calibration models were generated to predict drug contents of the test tablets from the spectral data. For the prediction of tablet hardness, two ANN calibration models (one each with 10 and 160 inputs) and two 4-factor PLS calibration models were generated and used to predict the hardness of test tablets. The PLS calibration models were generated using Vision software. Prediction of drug contents of test tablets using the ANN calibration models generated with 10 inputs was significantly better than the prediction obtained with the ANN calibration models with 160 inputs. For tablets with low drug concentrations (less than or equal to 2% w/w) prediction of drug content was better with either of the two ANN calibration models than with the PLS calibration models. However, prediction of drug contents of tablets with greater than or equal to 5% w/w drug was better with the PLS calibration models than with the ANN calibration models. Prediction of tablet hardness was better with the ANN calibration models generated with either 10 or 160 inputs than with the PLS calibration models. This work demonstrated that a well-trained ANN model is a powerful alternative technique for analysis of NIRS data. Moreover, the technique could be used in instances when the conventional modeling of data does not work adequately.

A comparison of reflectance and transmittance near-infrared spectroscopic techniques in determining drug content in intact tablets.

Drug contents of intact tablets were determined using non-destructive near infrared (NIR) reflectance and transmittance spectroscopic techniques. Tablets were compressed from blends of Avicel PH-101 and 0.5% w/w magnesium stearate with varying concentrations of anhydrous theophylline (0, 1, 2, 5, 10, 20 and 40% w/w). Ten tablets from each drug content batch were randomly selected for spectral analysis. Both reflectance and transmittance NIR spectra were obtained from these intact tablets. Actual drug contents of the tablets were then ascertained using a UV-spectrophotometer at 268 nm. Multiple linear regression (MLR) models at 1116 nm and partial least squares (PLS) calibration models were generated from the second derivative spectral data of the tablets in order to predict drug contents of intact tablets. Both the reflectance and the transmittance techniques were able to predict the drug contents in intact tablets over a wide range. However, a comparison of the results of the study indicated that the lowest percent errors of prediction were provided by the PLS calibration models generated from spectral data obtained using the transmittance technique.

Application of near-infrared spectroscopy for nondestructive analysis of Avicel powders and tablets.

The purpose of this study was to use near-infrared spectroscopy (NIRS) as a nondestructive technique to (a) differentiate three Avicel products (microcrystalline cellulose [MCC] PH-101, PH-102, and PH-200) in powdered form and in compressed tablets with and without 0.5% w/w magnesium stearate as a lubricant; (b) determine the magnesium stearate concentrations in the tablets; and (c) measure hardness of tablets compressed at several compression forces. Diffuse reflectance NIR spectra from Avicel powders and tablets (compression forces ranging from 0.2 to 1.2 tons) were collected and distance scores calculated from the second-derivative spectra were used to distinguish the different Avicel products. A multiple linear regression model was generated to determine magnesium stearate concentrations (from 0.25 to 2% w/w), and partial least squares (PLS) models were generated to predict hardness of tablets. The NIRS technique could distinguish between the three different Avicel products, irrespective of lubricant concentration, in both the powdered form and in the compressed tablets because of the differences in the particle size of the Avicel products. The percent error for predicting the lubricant concentration of tablets ranged from 0.2 to 10% w/w. The maximum percent error of prediction of hardness of tablets compressed at the various compression forces was 8.8% for MCC PH-101, 5.3% for MCC PH-102, and 4.6% for MCC PH-200. The NIRS nondestructive technique can be used to predict the Avicel type in both powdered and tablet forms as well as to predict the lubricant concentration and hardness.

Determination of copolymer ratios of poly(lactide-co-glycolide) using near-infrared spectroscopy.

The near infrared (NIR) spectroscopic technique was used to determine copolymer ratios of polylactide-co-glycolide samples. Appropriate quantities of DL-polylactic acid and lactic-co-glycolic acid polymers with 86:14, 75:25, 64:36 and 52:48 lactide to glycolide ratios were dissolved in methylene chloride to obtain 5% (w/w) solutions. NIR spectra of the samples were obtained from the solutions using a Polyol Analyzer operated in the transmittance mode. Linear regression calibration models were generated at 2130 and 2288 nm from the second derivative spectral data obtained from the NIR technique. The lowest and highest standard errors of calibration (SEC) at 2130 nm were 1.29 and 1.63%, whereas those obtained from the calibration models generated at 2288 nm were 2.00 and 2.03%, respectively. Partial least squares (PLS) calibration models were also generated from the second derivative spectral data from 1100 to 2500 nm. The lowest and the highest SEC for the models were 1.46 and 1.53%, respectively. The calibration models were then used to predict the lactide contents of the unknown (test) samples. The highest percent error of prediction was 2.56% for samples with 86% lactide content when the linear regression calibration at 2130 nm was used, whereas the highest percent error of prediction was 1.56% for samples with 64% lactide content when the linear regression calibration at 2288 nm was used. The highest percent error of prediction was 1.73% for samples with 75% lactide content when the two-factor PLS calibration model was used.

Controlled release of a contraceptive steroid from biodegradable and injectable gel formulations: in vitro evaluation.

PURPOSE: The purpose of this study was to investigate the effects of formulation factors including varying wax concentration, drug loading and drug particle size, on drug release characteristics from both pure oil and gel formulations prepared with a combination of derivatized vegetable oil (Labrafil 1944 CS) and glyceryl palmitostearate (Precirol ATO 5), using levonorgestrel as a model drug. METHODS: The effects of varying drug loadings, different drug particle sizes, and wax (Precirol) concentrations on in-vitro drug release rates were evaluated, and the mechanisms of drug release from the gels were determined. RESULTS: Zero-order drug release rates from the 10% Precirol gel formulations containing 0.25, 0.50 and 2.00% w/v drug loadings were lower than those observed for oil formulations containing identical drug loadings. Higher zero-order release rates were observed from formulations containing smaller drug particles suspended in both oil and gel formulations. The mechanism of drug release from gels containing less than 0.25% w/w drug was diffusion-controlled. Increasing the wax concentrations in the gels from 5% w/w to 20% w/w significantly decreased the diffusivity of the drug through the gel formulations and markedly increased the force required to inject the gels from two different sizes of needles. CONCLUSIONS: This study shows how modification of the physicochemical properties of the gel formulations by changing the drug particle size, wax concentration and drug loading, affects drug release characteristics from the system.

Controlled release of contraceptive steroids from biodegradable and injectable gel formulations: in vivo evaluation.

PURPOSE: The purpose of this study was to investigate in vivo biocompatibility, biodegradability and biological effects of contraceptive steroids, such as levonorgestrel and ethinyl estradiol, released from gels prepared with a combination of derivatized vegetable oil (Labrafil 1944 CS) and glyceryl ester of fatty acids (Precirol ATO 5). METHODS: Biocompatibility, biodegradability, and in vivo effects of levonorgestrel and ethinyl estradiol were studied by histologic evaluation of rat tissue, visual estimate of changes in gel size, and assessment of drug effects on reproductive cyclicity of female rats, respectively, following subcutaneous injection of gel formulations. RESULTS: Histological evaluation of the tissue samples following an injection of the gel revealed an inflammatory reaction for about 7 days, after which the tissues did not show any inflammatory response. Complete degradation of the gels containing 10% wax was observed between 5 and 6 weeks. Normal rat estrous cycles were completely blocked by the contraceptive steroids released from the gels. Gel formulations containing 0.25% w/w levonorgestrel were more effective in blocking the estrous cycle of female rats compared to the oil formulations containing an identical drug loading. The duration of the biological effect induced by levonorgestrel appears to be dose-related. The gel formulation containing 2.00% ethinyl estradiol was superior to oil formulation containing an identical drug loading in terms of controlling drug release and toxicity. CONCLUSIONS: These observations suggest that Labrafil-Precirol gels are biocompatible and biodegradable. Moreover, controlled release of steroids is possible in vivo for a prolonged period of time.

Effect of varying drug loading on particle size distribution and drug release kinetics of verapamil hydrochloride microspheres prepared with cellulose esters.

Microspheres containing two different drug loadings of a calcium channel blocker, verapamil hydrochloride, were prepared with three different cellulose esters namely cellulose acetate (CA), cellulose acetate propionate (CAP) and cellulose acetate butyrate (CAB) of approximately similar molecular weights using the emulsion-solvent evaporation method. Increasing the drug loading from 33.3 to 50% w/w increased the geometric mean diameter of the microspheres as well as the T50% values, i.e. time required to release 50% of the drug from microspheres prepared with all the three cellulose esters. Drug release from the microspheres was affected by the nature of polymer. Mathematical modelling of drug release data by fitting the data to various equations revealed that the data did not fit the conventional Higuchi's and Baker-Lonsdale's models for drug release from spherical matrices. Instead, the data fitted the log-probability and the Weibull models quite well.

Evaluation of Preflo modified starches as new direct compression excipients. I. Tabletting characteristics.

This investigation evaluated some new (Preflo) and existing commercially available (Starch 1500, Star Tab) modified starches as direct compression excipients. Preflo corn starches (CH-10, CH-20, CH-30) and Preflo potato starches (P-250, PI-10, PJ-20) were evaluated and compared with respect to their pharmaceutical properties such as particle size, density, flowability, friability, and compression properties. Preflo starches showed a high bulk density and good flowability. Preflo corn starches and Star Tab formed harder tablets than Preflo potato starches and Starch 1500. Data from the Athy-Heckel plots indicated that the Preflo starches are soft materials and, unlike Starch 1500, undergo plastic deformation. Tablets containing acetaminophen were also compressed with the starches and disintegration and dissolution studies were conducted. Starch 1500 tablets disintegrated in 3.5 min, whereas none of the Preflo starch tablets disintegrated in 30 min. While complete acetaminophen release occurred in 25 min from Starch 1500 tablets, the drug dissolution time from Preflo starch tablets varied from 4 to 12 hr, indicating a potential use for some of these starches in solid oral modified-release dosage forms.

Effect of drug loading and molecular weight of cellulose acetate propionate on the release characteristics of theophylline microspheres.

Microspheres with 40, 50, and 60% drug loading of anhydrous theophylline core material were prepared by the emulsion-solvent evaporation method. Three different molecular weights of cellulose acetate propionate were used as encapsulating polymers. The geometric mean diameter of the microspheres increased with drug loading for all polymers. Dissolution rate for a given particle size fraction also increased with drug loading for all polymers. Higuchi/Baker-Lonsdale spherical matrix dissolution kinetics were followed by narrow particle size fractions of the microspheres. A linear relationship between the T-50% (time required for 50% of the drug to be released) and the square of microsphere diameter was observed with all three molecular weights of the encapsulants. The slowest drug release was obtained with the high molecular weight polymer, which also produced the smoothest microspheres.

Effect of moisture content on compression properties of two dextrose-based directly compressible diluents.

Moisture sorption characteristics and the effect of moisture content on the compression properties of two dextrose-based directly compressible diluents, namely, Emdex (diluent A) and Sweetrex (diluent B) were studied. Both diluents sorbed moisture rapidly at relative humidities greater than 60%. For both the diluents, pressures required to compress tablets to the same relative density decreased with increasing moisture content. Yield pressures calculated from linear Heckel plots obtained from the compression data of both diluents reflected decreasing values with increasing moisture content. Three-way surface profile graphs of moisture content versus tablet parameters such as crushing force, relative density, and compression pressure give a unique overall picture of the compression properties of a diluent and offer the tablet formulator a useful tool for diluent comparison.

Effect of drug (core) particle size on the dissolution of theophylline from microspheres made from low molecular weight cellulose acetate propionate.

Three particle sizes (450, 120, and 5 microns) of theophylline were encapsulated in low molecular weight cellulose acetate propionate (intrinsic viscosity, 1.08 dl/g) by the solvent evaporation method. The theoretical drug content for all the batches of microspheres was 50% (w/w). Particle size analysis revealed that about 50% of the microspheres containing the large theophylline crystals (average length of 450 microns) were greater than 500 microns in diameter, whereas only about 35% of the microspheres containing the medium drug crystals (average length of 120 microns) were greater than 500 microns in diameter. The drug content of the larger microspheres prepared from the large drug crystals and the medium drug crystals was much greater than the theoretical drug content (50%, w/w); however, the drug content of all the batches of microspheres containing micronized drug was close to 50% (w/w). Release of the drug in simulated intestinal fluid was very rapid from microspheres containing large and medium drug crystals, while release was slower and more predictable from microspheres made from micronized drug.