Multivariate chemometric approach to fiber-optic dissolution testing

The use of fiber optics in in vitro dissolution testing opens up new possibilities for more powerful data evaluation since an entire UV-Vis spectrum can be collected at each measuring point. This paper illustrates a multivariate chemometric approach to the solution of problems of interfering absorbance of excipients in in vitro dissolution testing. Two different chemometric approaches are tested: multivariate calibration using partial least squares (PLS) regression and curve resolution using multivariate curve resolution alternating least squares (MCR-ALS), generalized rank annihilation (GRAM), and parallel factor analysis (PARAFAC). Multivariate calibration (PLS) can, following the construction of a calibration model from a calibration sample set, give selective and accurate determinations of the active ingredient in dissolution testing despite the presence of interfering absorbance from excipients. Curve resolution (MCR-ALS, GRAM, or PARAFAC) can be applied to dissolution testing data in order to determine the dissolution rate profiles and spectra for the interfering excipients as well as for the active ingredient without any precalibration. The concept of the application of these chemometric methods to fiber-optic dissolution testing data is exemplified by analysis of glibenclamide tablets enclosed in hard gelatin capsules. The results show that, despite highly overlapping spectra and unresolved raw data, it is possible with PLS to obtain an accurate dissolution rate profile of glibenclamide. Applying curve resolution makes it possible to obtain accurate estimates of both dissolution rate profiles and spectra of both the gelatin capsule and the glibenclamide. The application of multivariate chemometric methods to fiber-optic dissolution testing brings a fresh scope for a deeper understanding of in vitro dissolution testing, solving the problem of interfering absorbance of excipients and making it possible to obtain dissolution rate profiles and spectra of these. Obtaining dissolution rate profiles of multiple active pharmaceutical ingredients in tablets consisting of several active compounds is another possibility.     

Evaluation and comparison of five matrix excipients for the controlled release of acrivastine and pseudoephedrine

For treatment of allergic rhinitis, acrivastine with pseudoephedrine in Semprex®-D conventional capsules requires dosing every 6-8 hours. This study was designed to develop a controlled release matrix tablet of acrivastine and pseudoephedrine and evaluate 5 different matrix excipients for their in vitro controlled-release profiles. Compritol® 888ATO, Eudragit® RS, Methocel® K100M, Polyox® WSR301 and Precirol® ATO5 were used alone or in varying combinations for the formulation of controlled release matrix tablets. In vitro drug dissolution and mathematical modeling were used to characterize drug release rate and extent. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. Due to the aqueous solubility of pseudoephedrine and the size of the dose, none of the matrix excipients used alone prolonged drug release significantly to meet the desired twice-daily administration frequency. The use of two excipients in combination, however, significantly decreased the dissolution rate of both active ingredients. A combined lipid-based Compritol® and hydrophilic Methocel® produced optimal controlled drug release for longer than 8 hours for both acrivastine and pseudoephedrine.     

Development of an Implantable,Biodegradable, Controlled Drug Delivery System for Local Antibiotic Therapy

Abstract

A novel drug delivery system was developed using a monoglyceride (Glycerol Monostearate) and a water-soluble release rate modifier as the matrix. Cefuroxime sodium (Zinacef®) was chosen as a model drug in this study. Formulations (cylindrical implants 6 × 6 mm) were prepared by a melt-dispersion method. Dissolution studies were performed using USP paddle method. The effect of glycerol, PEG 400 and their combination on drug release profiles was studied. Two assay methods (UV and HPLC) for cefuroxime analysis were compared. Percent recovery from four formulations (A-D) was higher with UV than HPLC assay. While both UV and HPLC assay methods were developed for cefuroxime, only HPLC assay is stability indicating. Glycerol showed higher accelerating effect than PEG 400 on the drug release. All formulations exhibited extended release of cefuroxime. Degradation of cefuroxime occurred mainly during dissolution suggesting drug stability in the formulations.     

Different Types of Direct Compressible Excipients Affecting the Release Behavior of Theophylline Controlled-release Tablets Containing Eudragit Resins

Theophylline released from direct-compressed tablets containing Eudragit RSPM/RLPM and different types of direct compressible excipients was investigated. The influences of the type of dissolution medium and stirring speed on the release behavior of theophylline were also studied. The results showed that the type of direct compressible excipients, dissolution medium and stirring conditions significantly influenced the dissolution rate. The tablet made by dicalcium phosphate or microcrystalline cellulose exhibited the most controlled-release behavior. Almost all the release kinetics of tablets followed a Fickian-transport model.     

The use of optimazation techniques in pharmaceutical development

The lecture uses selected examples to illustrate the use of mathematical methods to optimize drug dosage forms:

Elucidation of compatibility between active ingredient and excipients required in the preformulation phase by factorial design.

Calculation of maximum allowable mean of particle sizes for active ingredient and the sum of auxiliary materials to achieve a sufficient content uniformity by applying the Stange-Pool equation.

Application of surface response research for identification of the working point in an “innocuous area of landscape” for scaling ups, handing over to production, of trouble shooting by using central composite desing and in the case of multiple constraints doing computerized grid search.

Only mentioned and not described in detail will be the methods for pharmacokinetical optimization, necessary for the development of modified release formulations.

Of course not for every development it is mandatory to use surface response research to get the necessary quality. But it is worthwile to apply refgularly factorial design for compatibility studies to calculate the necessary particle sizes and to compare in vivo results with dissolution rate data.     

Different Types of Direct Compressible Excipients Affecting the Release Behavior of Theophylline Controlled-release Tablets Containing Eudragit Resins

Abstract

Theophylline released from direct-compressed tablets containing Eudragit RSPM/RLPM and different types of direct compressible excipients was investigated. The influences of the type of dissolution medium and stirring speed on the release behavior of theophylline were also studied. The results showed that the type of direct compressible excipients, dissolution medium and stirring conditions significantly influenced the dissolution rate. The tablet made by dicalcium phosphate or microcrystalline cellulose exhibited the most controlled-release behavior. Almost all the release kinetics of tablets followed a Fickian-transport model.     

Selective imaging of active pharmaceutical ingredients in powdered blends with common excipients utilizing two-photon excited ultraviolet-fluorescence and ultraviolet-second order nonlinear optical imaging of chiral crystals

Second order nonlinear optical imaging of chiral crystals (SONICC) and two-photon excited fluorescence measurements [both autofluorescence and two-photon excited UV-fluorescence (TPE-UVF)] were assessed for the selective detection of APIs relative to common pharmaceutical excipients. Active pharmaceutical ingredients (APIs) compose only a small percentage of most tabulated formulations, yet the API distribution within the tablet can affect drug release and tablet stability. Complementary measurements using either UV-SONICC (266 nm detection) or TPE-UVF were shown to generate signals >50-fold more intense for a model API (griseofulvin) than those produced by common pharmaceutical excipients. The combined product of the measurements produced signals >10(4)-fold greater than the excipients studied. UV-SONICC or TPE-UVF produced greater selectivity than analogous measurements with visible-light detection, attributed to the presence of aromatic moieties within the API exhibiting strong one and two photon absorption at ~266 nm. Complementary SONICC and fluorescence measurements allowed for the sensitive detection of the three-dimensional distribution of tadalafil within a Cialis tablet to a depth of >140 μm.     

The use of optimazation techniques in pharmaceutical development

Abstract

The lecture uses selected examples to illustrate the use of mathematical methods to optimize drug dosage forms:

Elucidation of compatibility between active ingredient and excipients required in the preformulation phase by factorial design.

Calculation of maximum allowable mean of particle sizes for active ingredient and the sum of auxiliary materials to achieve a sufficient content uniformity by applying the Stange-Pool equation.

Application of surface response research for identification of the working point in an “innocuous area of landscape” for scaling ups, handing over to production, of trouble shooting by using central composite desing and in the case of multiple constraints doing computerized grid search.

Only mentioned and not described in detail will be the methods for pharmacokinetical optimization, necessary for the development of modified release formulations.

Of course not for every development it is mandatory to use surface response research to get the necessary quality. But it is worthwile to apply refgularly factorial design for compatibility studies to calculate the necessary particle sizes and to compare in vivo results with dissolution rate data.     

Influence of drug load on dissolution behavior of tablets containing a poorly water-soluble drug: estimation of the percolation threshold

Drug load plays an important role in the development of solid dosage forms, since it can significantly influence both processability and final product properties. The percolation threshold of the active pharmaceutical ingredient (API) corresponds to a critical concentration, above which an abrupt change in drug product characteristics can occur. The objective of this study was to identify the percolation threshold of a poorly water-soluble drug with regard to the dissolution behavior from immediate release tablets. The influence of the API particle size on the percolation threshold was also studied. Formulations with increasing drug loads were manufactured via roll compaction using constant process parameters and subsequent tableting. Drug dissolution was investigated in biorelevant medium. The percolation threshold was estimated via a model dependent and a model independent method based on the dissolution data. The intragranular concentration of mefenamic acid had a significant effect on granules and tablet characteristics, such as particle size distribution, compactibility and tablet disintegration. Increasing the intragranular drug concentration of the tablets resulted in lower dissolution rates. A percolation threshold of approximately 20% v/v could be determined for both particle sizes of the API above which an abrupt decrease of the dissolution rate occurred. However, the increasing drug load had a more pronounced effect on dissolution rate of tablets containing the micronized API, which can be attributed to the high agglomeration tendency of micronized substances during manufacturing steps, such as roll compaction and tableting. Both methods that were applied for the estimation of percolation threshold provided comparable values.     

Formulation Studies of Furosemide-Amiloride HCI Combination Tablets

Abstract

During the formulation studies of a furosemide-amiloride HCl combination tablet, an unexpected interaction between the two drugs was encountered. The drugs tended to form aggregates when in contact with the dissolution medium during dissolution testing. This phenomenon decreased the dissolution of both actives significantly. Various formulas were tried to eliminate this problem. Granulation of the formulation with povidone produced a tablet with good dissolution properties. A possible mechanism for preventing the formation of furosemide-amiloride HCl aggregates in the presence of povidone is described.     

Pharmaceutical quantification with univariate analysis using transmission Raman spectroscopy

The purpose of this study was to investigate the quantification performance of transmission Raman spectroscopy with univariate analysis. Model dosage forms containing acetaminophen and an excipient, lactose monohydrate, were prepared. The Raman spectra of the tablets were obtained using the modes of transmission, backscattering micro-spectroscopy, and wide area illumination. Calibration curves for quantification of acetaminophen in the tablets were created using peak heights of the Raman spectra. Of the three modes of measurement, the quantitative results by transmission had the highest correlation with those by conventional UV–vis methods. In the validation of quantification by the transmission mode with univariate analysis, a certain degree of daily variation was confirmed. Additionally, quantitative results using peak heights were compared with those of partial least squares (PLSs) multivariate analysis. The root mean square error of prediction (RMSEP) suggested that quantification using PLS provided better precision than the peak height method as expected. However, content uniformity test using large sample sizes by the Raman spectra is not required to be very highly predictive because they usually employ non-parametric criteria and include wide specification ranges. Therefore, univariate analysis using transmission Raman spectroscopy was a suitable quantitative method for conducting content uniformity tests of large sample sizes.     

The development of a modified dissolution method suitable for investigating powder mixtures

A novel dissolution method was developed, suitable for powder mixtures, based on the USP basket apparatus. The baskets were modified such that the powder mixtures were retained within the baskets and not dispersed, a potential difficulty that may arise when using conventional USP basket and paddle apparatus. The advantages of this method were that the components of the mixtures were maintained in close proximity, maximizing any drug: excipient interaction and leading to more linear dissolution profiles. Two weakly acidic model drugs, ibuprofen and acetaminophen, and a selection of pharmaceutical excipients, including potential dissolution-enhancing alkalizing agents, were chosen for investigation. Dissolution profiles were obtained for simple physical mixtures. The f1 fit factor values, calculated using pure drug as the reference material, demonstrated a trend in line with expectations, with several dissolution enhancers apparent for both drugs. Also, the dissolution rates were linear over substantial parts of the profiles. For both drugs, a rank order comparison between the f1 fit factor and calculated dissolution rate, obtained from the linear section of the dissolution profile, demonstrated a correlation using a significance level of P = 0.05. The method was proven to be suitable for discriminating between the effects of excipients on the dissolution of the model drugs. The method design produced dissolution profiles where the dissolution rate was linear for a substantial time, allowing determination of the dissolution rate without mathematical transformation of the data. This method may be suitable as a preliminary excipient-screening tool in the drug formulation development process.     

Nanoparticle Engineering Processes for Enhancing the Dissolution Rates of Poorly Water Soluble Drugs

Poor water solubility is an industry wide issue, especially for pharmaceutical scientists in drug discovery and drug development. In recent years, nanoparticle engineering processes have become promising approaches for the enhancement of dissolution rates of poorly water soluble drugs. Nanoparticle engineering enables manufacturing of poorly water soluble drugs into nanoparticles alone, or incorporation with a combination of pharmaceutical excipients. The use of these processes has dramatically improved in vitro dissolution rates and in vivo bioavailabilities of many poorly water soluble drugs. This review highlights several commercially or potentially commercially available nanoparticle engineering processes recently reported in the literature for increasing the dissolution properties of poorly water soluble drugs.     

Nanoparticle engineering processes for enhancing the dissolution rates of poorly water soluble drugs

Poor water solubility is an industry wide issue, especially for pharmaceutical scientists in drug discovery and drug development. In recent years, nanoparticle engineering processes have become promising approaches for the enhancement of dissolution rates of poorly water soluble drugs. Nanoparticle engineering enables manufacturing of poorly water soluble drugs into nanoparticles alone, or incorporation with a combination of pharmaceutical excipients. The use of these processes has dramatically improved in vitro dissolution rates and in vivo bioavailabilities of many poorly water soluble drugs. This review highlights several commercially or potentially commercially available nanoparticle engineering processes recently reported in the literature for increasing the dissolution properties of poorly water soluble drugs.     

Near-infrared spectroscopic applications in pharmaceutical particle technology

Abstract

Near-infrared spectroscopy (NIRS) is nowadays an established analytical technique in the pharmaceutical industry. The aim of this review is to present the progress of NIRS in providing useful information for pharmaceutical particle technology. NIR methods are now developed to characterize a wide variety of materials (active pharmaceutical ingredients, excipients, co-processed powders, and physical mixtures) and pharmaceutical dosage forms (conventional, modified drug release technologies, and phytomedicines). This review also provides a number of spectra to illustrate the fundamental understanding of NIRS which has been gained. The sampling that must occur prior to the acquisition of near-infrared spectra is also discussed, as well as developments in monitoring mixing, tableting, and coating. This review will be valuable for product formulation and process engineering specialists.     

Quantitative determination of acetaminophen in pharmaceutical formulations using differential scanning calorimetry. Comparison with spectrophotometric method

In this paper our previous researches dealing with compatibility, thermoanalytical characterization, the kinetics of thermal degradation of acetaminophen, either pure or contained in some commercial pharmaceutical formulations, have found applications outlets. In a previous investigation the possible interactions between acetaminophen and four excipients contained in the commercial pharmaceutical formulations were tested. As a continuation of this research in the present study an analytical method based on differential scanning calorimetry (DSC) was applied to determine the acetaminophen content of four commercial pharmaceutical formulations. For a fifth drug it was shown that the method is not applicable owing to observed incompatibility with one of the excipients. Finally, the analytical results obtained were compared with those derived from two UV spectrophotometric methods (one, i.e., “direct method,” recommended by the Pharmacopeia and the other based on the first-order derivative UV spectra).     

Quantitative Determination of Acetaminophen in Pharmaceutical Formulations Using Differential Scanning Calorimetry. Comparison with Spectrophotometric Method

In this paper our previous researches dealing with compatibility, thermoanalytical characterization, the kinetics of thermal degradation of acetaminophen, either pure or contained in some commercial pharmaceutical formulations, have found applications outlets. In a previous investigation the possible interactions between acetaminophen and four excipients contained in the commercial pharmaceutical formulations were tested. As a continuation of this research in the present study an analytical method based on differential scanning calorimetry (DSC) was applied to determine the acetaminophen content of four commercial pharmaceutical formulations. For a fifth drug it was shown that the method is not applicable owing to observed incompatibility with one of the excipients. Finally, the analytical results obtained were compared with those derived from two UV spectrophotometric methods (one, i.e., “direct method,” recommended by the Pharmacopeia and the other based on the first-order derivative UV spectra).     

Bead compacts. II. Evaluation of rapidly disintegrating nonsegregating compressed bead formulations

In this study, three techniques for the prevention or mitigation of polymer coat fracture on compaction of sustained-release beads into tablets were investigated. All techniques in this paper were evaluated without the addition of any cushioning excipients, but rather by spray coating these excipients to avoid segregation during product manufacturing. First, it was shown that use of swellable polymers such as polyethylene oxide (PEO) serves a unique and effective role in preventing polymer coat rupture. PEO was spray coated between the ethylcellulose (EC) and microcrystalline cellulose (MCC) coats to evaluate its cushioning effect. The compacted PEO layered beads, on dissolution, disintegrated into individual beads with sustained drug release of up to 8 hr. It is postulated that the PEO was hydrated and formed a gel that acts as a sealant for the cracks formed in the ruptured polymer coating (sealant-effect compacts). Second, EC-coated drug-layered beads were also overcoated with cushioning excipients such as polyethylene glycol (PEG) and MCC with an additional coating of a disintegrant. These beads were compressed at pressures of 125, 500, and 1000 pounds into caplets and, on dissolution testing, disintegrated into individual beads when the dissolution medium was switched from simulated gastric to intestinal fluid. The dissolution profiles show that the polymer coat was partly disrupted on compaction, leading to a total drug release in 8-10 hr. Third, EC-coated beads were also granulated with cushioning excipient and compressed. This approach also resulted in a ruptured polymer coat on the beads, but at higher compaction pressure produced a partially disintegrating matrix caplet that showed a nearly zero-order sustained drug release for 24 hr. The effect of bead size and polymer coat thickness was also investigated.     

A method for quantification from composite spectra: application to the determination of isomeric DNA photoproducts by tandem mass spectrometry

Quantification of mixture components from their composite optical or mass spectra is a common need in analytical chemistry. We encountered the need when applying a combination of enzymatic digestion with nuclease P1 and tandem mass spectrometry to a mixture of isomeric photomodified oligodeoxynucleotides. In the procedure, we collisionally activated the [M - H]- or [M + Na - 2H]- ion of trinucleotide triphosphates, which were extricated enzymatically from the larger, damaged oligodeoxynucleotides, and we measured the relative abundances of characteristic fragment ions. The results sometimes yield curved calibrations for plots of the relative fragment ion abundances in the product ion spectra of isomers versus their relative amounts. We developed a normalized linear model, which brings understanding to the nonlinear plots and allows quantification of the mixture components from their composite spectra. The outcome demonstrates a general quantification procedure and shows that different yields for generating fragment ions from different constituents of the mixture cause the curved calibration lines.     

Advantages of the Use of Very Short and Ultra Short Hplc Columns for Drug Analysis in Dissolution Testing

The advantages of short (3–5cm long) or ultra short (4mm long) HPLC columns for drug analysis in dissolution testing are illustrated by reference to some example antihypertensive drug formulations.

Advantages include: selectivity, where interfering excipients or co-formulated drugs complicate UV spectrophotometric analysis: time savings, compared with conventional HPLC columns (although where UV spectrophotometry is applicable no time advantages may be obtained with short column HPLC): economy, as the columns are less expensive than conventional columns and there is reduced solvent consumption: increased sensitivity compared with conventional columns. Low dose potent. drugs with poor chromophores may be more readily quantitated: amenity to automation, including the use of laboratory robots.

These advantages would suggest the wide applicability to this mode of analysis in dissolution testing.