Prediction of dissolution profiles by non-destructive NIR spectroscopy in bilayer tablets.

This study describes how near infrared (NIR) spectroscopy can be used to predict the dissolution of bilayer tablets as a non-destructive approach. Tablets in this study consist of two active pharmaceutical ingredients (APIs) physically separated in layers and manufactured under three levels of hardness. NIR spectra were individually acquired for both layers in diffuse reflectance mode. Reference dissolution profile values were obtained using dissolution apparatus & HPLC. A multivariate partial least squares (PLS) calibration model was developed for each API relating its dissolution profile to spectral data. This calibration model was used to predict dissolution profiles of an independent test set and results of the prediction were compared using model free approaches i.e. dissimilarity (f1) & similarity (f2) factors to assure similarity in dissolution performance.

Enabling real time release testing by NIR prediction of dissolution of tablets made by continuous direct compression (CDC).

A method for predicting dissolution profiles of directly compressed tablets for a fixed sustained release formulation manufactured in a continuous direct compaction (CDC) system is presented. The methodology enables real-time release testing (RTRt). Tablets were made at a target drug concentration of 9% Acetaminophen, containing 90% lactose and 1% Magnesium Stearate, and at a target compression force of 24kN. A model for predicting dissolution profiles was developed using a 3(4-1) fractional factorial experimental design built around this targeted condition. Four variables were included: API concentration (low, medium, high), blender speed (150rpm, 200rpm, 250rpm), feed frame speed (20rpm, 25rpm, 30rpm), compaction force (8KN, 16KN, 24KN). The tablets thus obtained were scanned at-line in transmission mode using Near IR spectroscopy. The dissolution profiles were described using two approaches, a model-independent "shape and level" method, and a model-dependent approach based on Weibull's model. Multivariate regression was built between the NIR scores as the predictor variables and the dissolution profile parameters as the response. The model successfully predicted the dissolution profiles of the individual tablets (similarity factor, f2 ∼72) manufactured at the targeted set point. This is a first ever published manuscript addressing RTRt for dissolution prediction in continuous manufacturing, a novel and state of art technique for tablet manufacturing.

Prediction of dissolution profiles by non-destructive near infrared spectroscopy in tablets subjected to different levels of strain.

This study describes how the strain on formulation components affects dissolution and how near infrared spectroscopy can be used to predict dissolution. Strain (exposure to shear stress) applied during powder mixing affects the interaction between formulation components. Particles experience shear strain when they move relative to each other in a process affecting the properties of the final product. This stress affects the dissolution of oral solid dosages forms. However, dissolution testing destroys the entire tablet, making it impossible to further evaluate tablet properties when an out of specification result is obtained. Thus, a nondestructive technique such as near infrared spectroscopy is desirable to predict dissolution. The aim of this study was to predict dissolution on tablets with different levels of strain (shear) using near infrared spectroscopy in combination with multivariate data analysis. Shear was induced using a modified Couette cell on the powder mixture and tablets from these mixtures were produced using a tablet press emulator. Tablets produced with different strain levels were measured using near infrared spectroscopy. Spectra were obtained in diffuse reflectance mode and pretreated with baseline correction to maintain the physical and chemical information of the tablets. Dissolution profiles were obtained using USP Apparatus 2 as a reference method. Principal component analysis was used to study the sources of variation in the spectra obtained. Partial least squares 2 was used to predict dissolution on tablets with different levels of strain.

Statistical comparison of dissolution profiles.

Statistical methods to assess similarity of dissolution profiles are introduced. Sixteen groups of dissolution profiles from a full factorial design were used to demonstrate implementation details. Variables in the design include drug strength, tablet stability time, and dissolution testing condition. The 16 groups were considered similar when compared using the similarity factor f2 (f2 > 50). However, multivariate ANOVA (MANOVA) repeated measures suggested statistical differences. A modified principal component analysis (PCA) was used to describe the dissolution curves in terms of level and shape. The advantage of the modified PCA approach is that the calculated shape principal components will not be confounded by level effect. Effect size test using omega-squared was also used for dissolution comparisons. Effects indicated by omega-squared are independent of sample size and are a necessary supplement to p value reported from the MANOVA table. Methods to compare multiple groups show that product strength and dissolution testing condition had significant effects on both level and shape. For pairwise analysis, a post-hoc analysis using Tukey's method categorized three similar groups, and was consistent with level-shape analysis. All these methods provide valuable information that is missed using f2 method alone to compare average profiles. The improved statistical analysis approach introduced here enables one to better ascertain both statistical significance and clinical relevance, supporting more objective regulatory decisions.

Using USP I and USP IV for discriminating dissolution rates of nano- and microparticle-loaded pharmaceutical strip-films.

Recent interest in the development of drug particle-laden strip-films suggests the need for establishing standard regulatory tests for their dissolution. In this work, we consider the dissolution testing of griseofulvin (GF) particles, a poorly water-soluble compound, incorporated into a strip-film dosage form. The basket apparatus (USP I) and the flow-through cell dissolution apparatus (USP IV) were employed using 0.54% sodium dodecyl sulfate as the dissolution medium as per USP standard. Different rotational speeds and dissolution volumes were tested for the basket method while different cell patterns/strip-film position and dissolution media flow rate were tested using the flow-through cell dissolution method. The USP I was not able to discriminate dissolution of GF particles with respect to particle size. On the other hand, in the USP IV, GF nanoparticles incorporated in strip-films exhibited enhancement in dissolution rates and dissolution extent compared with GF microparticles incorporated in strip-films. Within the range of patterns and flow rates used, the optimal discrimination behavior was obtained when the strip-film was layered between glass beads and a flow rate of 16 ml/min was used. These results demonstrate the superior discriminatory power of the USP IV and suggest that it could be employed as a testing device in the development of strip-films containing drug nanoparticles.

Electrodeless electrohydrodynamic drop-on-demand encapsulation of drugs into porous polymer films for fabrication of personalized dosage units.

Noncontact drop-on-demand (DOD) dosing is a promising strategy for manufacturing of personalized dosage units. However, current DOD methods developed for printing chemically and thermally stable, low-viscosity inks are of limited use for pharmaceuticals due to fundamentally different functional requirements. To overcome their deficiency, we developed a novel electrohydrodynamic (EHD) DOD (Appl, Phys, Lett. 97, 233501, 2010) that operates on fluids of up to 30 Pa·s in viscosity over a wide range of droplet sizes and provides a precise control over the droplet volume. We now evaluate the EHD DOD as a method for fabrication of dosage units by printing drug solutions on porous polymer films prepared by freeze-drying. Experiments were carried out on ibuprofen and griseofulvin, as model poorly water-soluble drugs, polyethylene glycol 400, as a drug carrier, and hydroxypropyl methylcellulose films. The similarities between drug release profiles from different dosage units were assessed by model-independent difference, f(1) , and similarity, f(2) , factors. The results presented show that EHD DOD offers a powerful tool for the evolving field of small-scale pharmaceutical technologies for tailoring medicines to individual patient's needs by printing a vast array of predefined amounts of therapeutics arranged in a specific pattern on a porous film.

Improvement of tablet coating uniformity using a quality by design approach.

A combination of analytical and statistical methods is used to improve a tablet coating process guided by quality by design (QbD) principles. A solid dosage form product was found to intermittently exhibit bad taste. A suspected cause was the variability in coating thickness which could lead to the subject tasting the active ingredient in some tablets. A number of samples were analyzed using a laser-induced breakdown spectroscopy (LIBS)-based analytical method, and it was found that the main variability component was the tablet-to-tablet variability within a lot. Hence, it was inferred that the coating process (performed in a perforated rotating pan) required optimization. A set of designed experiments along with response surface modeling and kriging method were used to arrive at an optimal set of operating conditions. Effects of the amount of coating imparted, spray rate, pan rotation speed, and spray temperature were characterized. The results were quantified in terms of the relative standard deviation of tablet-averaged LIBS score and a coating variability index which was the ratio of the standard deviation of the tablet-averaged LIBS score and the weight gain of the tablets. The data-driven models developed based on the designed experiments predicted that the minimum value of this index would be obtained for a 6% weight gain for a pan operating at the highest speed at the maximum fill level while using the lowest spraying rate and temperature from the chosen parametric space. This systematic application of the QbD-based method resulted in an enhanced process understanding and reducing the coating variability by more than half.

Synthesis and immobilization of micro-scale drug particles in presence of ß-cyclodextrins.

The anti-solvent synthesis in presence of cyclodextrins (CDs) of the drug Griseofulvin (GF) is presented. This was followed by immobilization into cellulosic polymer films suitable for drug delivery. The results show that 72% of the GF precipitated in presence of CD, while the rest led to the formation of a water soluble GF/CD complex. The cyclodextrins were effective in inhibiting particle growth and stabilizing the drug suspensions. Among the CDs tested here, hydroxypropyl-ß-cyclodextrin (HPBCD) was found to be most effective in reducing the particle size. The release profiles from the cyclodextrin stabilized GF particles showed improvement in release rate, which indicated effective drug/cyclodextrin interactions.

Synthesis and immobilization of micro-scale drug particles in cellulosic films.

The anti-solvent synthesis of micron-scale particles, their stabilization, and subsequent self-assembly into polymer films suitable for drug delivery is presented. The colloidal particles were stabilized using low molecular weight hydroxypropyl methylcellulose (HPMC), while drug encapsulation was carried out with high molecular weight HPMC and polyvinylpyrrolidone (PVP). Griseofulvin (GF) was used as the model drug compound, and the polymer films were evaluated in terms of their surface morphology, mechanical properties and in vitro drug release. In general, the release rates were best described by first-order and Hixson-Crowell kinetic models, and in a typical film containing 57% HPMC, 100% of GF was released within 50 min.