A dimensionless variable for the scale up and transfer of a roller compaction formulation.

Roller compaction is the most commonly employed dry granulation process in the pharmaceutical industry. While this process is increasingly used as an alternative to wet granulation, there are no parameter sets or system of equations to quickly scale up or transfer a formulation between two pieces of equipment. In this work, dimensionless variable was examined as a method to transfer the operating parameters of a formulation between two different pieces of equipment. This work was completed to establish the ground work for the development of a dimensionless relationship relating the operating parameters of the equipment to the porosity of the ribbon. The working hypothesis was three-fold, namely (i) that ribbons of the same porosity made with different equipment will have similar properties, (ii) that it is possible to establish an objective relationship between ribbon porosity and a combination of operating parameters and raw material attributes and (iii) that by expressing such parameter combination as a dimensionless variable, it will be possible to use the same relationship for different pieces of roller compaction equipment. The dimensionless variable RP/RS*HFS*True Density*D2 was found to correlate well with the ribbon porosity for the formulations and equipment used in these experiments. Depending on the formulation, the average difference in ribbon porosity between the two units varied between 0.012 and 0.024.

The influence of API concentration on the roller compaction process: modeling and prediction of the post compacted ribbon, granule and tablet properties using multivariate data analysis.

OBJECTIVE: While previous research has demonstrated roller compaction operating parameters strongly influence the properties of the final product, a greater emphasis might be placed on the raw material attributes of the formulation. There were two main objectives to this study. First, to assess the effects of different process variables on the properties of the obtained ribbons and downstream granules produced from the rolled compacted ribbons. Second, was to establish if models obtained with formulations of one active pharmaceutical ingredient (API) could predict the properties of similar formulations in terms of the excipients used, but with a different API. MATERIALS AND METHODS: Tolmetin and acetaminophen, chosen for their different compaction properties, were roller compacted on Fitzpatrick roller compactor using the same formulation. Models created using tolmetin and tested using acetaminophen. The physical properties of the blends, ribbon, granule and tablet were characterized. Multivariate analysis using partial least squares was used to analyze all data. RESULTS: Multivariate models showed that the operating parameters and raw material attributes were essential in the prediction of ribbon porosity and post-milled particle size. The post compacted ribbon and granule attributes also significantly contributed to the prediction of the tablet tensile strength. CONCLUSIONS: Models derived using tolmetin could reasonably predict the ribbon porosity of a second API. After further processing, the post-milled ribbon and granules properties, rather than the physical attributes of the formulation were needed to predict downstream tablet properties. An understanding of the percolation threshold of the formulation significantly improved the predictive ability of the models.

Utility of multivariate analysis in modeling the effects of raw material properties and operating parameters on granule and ribbon properties prepared in roller compaction.

This article aimed to model the effects of raw material properties and roller compactor operating parameters (OPs) on the properties of roller compacted ribbons and granules with the aid of principal component analysis (PCA) and partial least squares (PLS) projection. A database of raw material properties was established through extensive physical and mechanical characterization of several microcrystalline cellulose (MCC) and lactose grades and their blends. A design of experiment (DoE) was used for ribbon production. PLS models constructed with only OP-modeled roller compaction (RC) responded poorly. Inclusion of raw material properties markedly improved the goodness of fit (R(2) = .897) and model predictability (Q(2) = 0.72).

Effect of the variation in the ambient moisture on the compaction behavior of powder undergoing roller-compaction and on the characteristics of tablets produced from the post-milled granules.

Effect of variation in the ambient moisture levels on the compaction behavior of a 10% acetaminophen (APAP) powder blend in microcrystalline cellulose (MCC) powder was studied by comparing the physical and mechanical properties of ribbons prepared by roller compaction with those of simulated ribbons, i.e., tablets prepared under uni-axial compression. Relative density, moisture content, tensile strength, and Young's modulus were used as key compact properties for comparison. Moisture was found to facilitate the particle rearrangement of both, the APAP and the MCC particles, as well as the deformation of the MCC particles. The tensile strength of the simulated ribbons also showed an increase with increasing moisture content. An interesting observation was that the tensile strength of the roller compacted samples first increased and then decreased with increasing moisture content. Variation in the ambient moisture during roller compaction was also found to influence the characteristics of tablets produced from the granules obtained post-milling the ribbons. A method to study this influence is also reported.

Influence of ambient moisture on the compaction behavior of microcrystalline cellulose powder undergoing uni-axial compression and roller-compaction: a comparative study using near-infrared spectroscopy.

This study evaluates the effect of variation in the ambient moisture on the compaction behavior of microcrystalline cellulose (MCC) powder. The study was conducted by comparing the physico-mechanical properties of, and the near infrared (NIR) spectra collected on, compacts prepared by roller compaction with those collected on simulated ribbons, that is, compacts prepared under uni-axial compression. Relative density, moisture content, tensile strength (TS), and Young modulus were used as key sample attributes for comparison. Samples prepared at constant roller compactor settings and feed mass showed constant density and a decrease in TS with increasing moisture content. Compacts prepared under uni-axial compression at constant pressure and compact mass showed the opposite effect, that is, density increased while TS remained almost constant with increasing moisture content. This suggests difference in the influence of moisture on the material under roller compaction, in which the roll gap (i.e., thickness and therefore density) remains almost constant, vs. under uni-axial compression, in which the thickness is free to change in response to the applied pressure. Key sample attributes were also related to the NIR spectra using multivariate data analysis by the partial least squares projection to latent structures (PLS). Good agreement was observed between the measured and the NIR-PLS predicted values for all key attributes for both, the roller compacted samples as well as the simulated ribbons.

Real-time near-infrared monitoring of content uniformity, moisture content, compact density, tensile strength, and Young's modulus of roller compacted powder blends.

A method for real-time in-line near-infrared (NIR) monitoring of roller compaction is reported. Multivariate analysis using partial least square projections to latent structures (PLS) was used to relate the spectral data with key compact attributes: content uniformity, moisture content, relative density, tensile strength, and Young's modulus. NIR calibration curves were generated using the spectral data collected on simulated ribbons, that is, tablets prepared under uni-axial compression, and tested on the data collected on another set of simulated ribbons and by monitoring the ribbons as they exited the roller compactor. For all compact attributes, the NIR predicted values agreed well with the values measured using a reference method.

Modeling and monitoring of polymorphic transformations during the drying phase of wet granulation.

PURPOSE: The purpose of this work was to monitor polymorphic transformations of glycine during the drying phase of a wet granulation and model the polymorphic conversions using a time-based reconciliation model. METHODS: Near-infrared spectroscopy (NIR) was used for quantitation of polymorphs, and X-ray powder diffraction (XRPD) was used for qualitative analysis of polymorphs. RESULTS: The data show that the faster the granulation was dried, the more kinetic trapping of the metastable alpha-glycine polymorph, as predicted by reconciliation of the time scales of both the drying rate and the rate of the solution-mediated conversion. CONCLUSIONS: By knowing basic properties of the drug substance (solubility of the polymorphic forms and the rate of the solution-mediated conversion), processing conditions, such as the drying rate, can be adjusted to anticipate and prevent potential polymorphic transformations.

Nondestructive measurements of the compact strength and the particle-size distribution after milling of roller compacted powders by near-infrared spectroscopy.

Compact strength and the particle-size distribution of milled roller compacted compacts were correlated to the slope of the best-fit line through near-infrared spectra for samples prepared under different roll speeds and feed rates. The above correlations were found to hold for compacts prepared from microcrystalline cellulose powder as well as from a typical direct compression pharmaceutical powder blend containing tolmetin sodium dihydrate, microcrystalline cellulose, and dicalcium phosphate dihydrate. Near-infrared spectra were also collected real time for the compacts prepared from the tolmetin powder blend. The real-time slope values for the spectra showed good agreement with the off-line data. The strength of compacts was determined using three-point beam bending method and the particle-size distribution of the milled compacts was determined using sieve analysis. The results suggest that the real-time values of the slope of the best-fit line through the near-infrared spectrum offers a robust, yet simple and fast quality control tool to monitor/control manufacturing and scale-up processes involving dry granulation by roller compaction.

In situ monitoring of wet granulation using online X-ray powder diffraction.

PURPOSE: Polymorphic transformations during the wet granulation of a metastable polymorph of flufenamic acid were monitored in situ using online X-ray powder diffraction. The resulting data were used in testing a proposed process induced transformation rate model, which allows the extent and occurrence of polymorphic transformations during wet granulation to be controlled by adjusting the granulation time. METHODS: A small-scale, top mixing granulator was designed for compatibility with novel X-ray powder diffraction equipment (available from X-Ray Optical Systems of East Greenbush, NY). RESULTS: The unique polycapillary optic and X-ray source allowed the transformation of the metastable to the stable polymorph to be followed during the granulation. Following a diffraction peak each for the metastable and stable forms demonstrated that polymorphic transformations during the wetting phase of granulation follow the trends predicted by the model. CONCLUSIONS: The advanced online monitoring may allow real-time control of the process by the adjustment of process parameters, such as granulation time, and clearly qualifies as a PAT (process analytical technology).

Investigating the effects of excipients on the powder flow characteristics of theophylline anhydrous powder formulations.

Pharmaceutical excipients may have a great effect on properties affecting tablet production. To determine if formulations containing theophylline anhydrous would have properties allowing them to be easily tableted, functional parameters affecting powder flow were evaluated. The Carr Flowability Indices were used for this evaluation. Formulations to be studied include theophylline anhydrous as the active ingredient, hydrous lactose and dicalcium phosphate dihydrate as diluents, polyvinylpyrrolidone as a binder, and fumed silica as a flow promoter. The effect of each component on powder flow is discussed.

Thermal porosity analysis of croscarmellose sodium and sodium starch glycolate by differential scanning calorimetry.

The aim of the study was to demonstrate the applicability of differential scanning calorimetry (DSC) on porosity analysis for cellulose and starch. Croscarmellose sodium (CCS) and sodium starch glycolate (SSG) were allowed to sorb moisture in 85%, 90%, 95%, and 100% relative humidity (RH) at 40 degrees C for 24 hours. The pretreated samples were then subjected to DSC running temperature ranging from 25 degrees C to -50 degrees C at a cooling rate of 10 degrees C/min. The cooling traces of water crystallization, if present, were transformed to porosity distribution via capillary condensation using Kelvin's equation. The porosity analysis of CCS and SSG was also done using nitrogen adsorption as a reference method. It was found that sorbed water could not be frozen (in cases of 85% and 90% RH) until the moisture content exceeded a cutoff value (in cases of 95% and 100% RH). The nonfreezable moisture content was referred to tightly bound, plasticizing water, whereas the frozen one may be attributed to loosely bound water condensation in pore structure of CCS and SSG surfaces. Not only capillary condensation but also the tightly bound, nonfreezable monolayer water lying along the inner pores of the surface contributed to porosity determination. Good agreement with less than 5% deviation of mean pore size was observed when the results were compared with nitrogen adsorption. The narrower pore size distributions, however, were obtained because of the limitations of the technique. It was concluded that pore analysis by DSC could be successful. Further research needs to be done to account for limitations and to extend the applicability of the technique.

Quantitative determination of polymorphic composition in intact compacts by parallel-beam X-ray powder diffractometry.

This paper details the development of a method using parallel-beam X-ray powder diffractometry as a novel means of determining polymorphic composition in intact compacts. Two polymorphic systems, chlorpropamide and glycine, were selected. The polymorphic components were weighed, mixed, and compressed using a Carver press with 3/8-in. concave tooling. The compacts were then analyzed using parallel-beam X-ray powder diffractometry in transmission geometry. The data were processed using the profile-fitting module in the Shimadzu XRD-6000 software V 4.1 (for NT 4.0/98). The integrated intensity ratio of a selected peak for each crystal form was used for quantitation of each polymorph. Excellent linear correlation was observed for both polymorphic systems. The convex shape of the compact surface had no effect on the XRD patterns. Since parallel-beam X-ray diffractometry is not sensitive to the shape of the sample surface, it provides a simple method for quantifying polymorphs in intact compacts. Further work to extend this to formulated tablets is ongoing. The relatively larger variation in one of the peaks in the chlorpropamide study was found to be consistent with the computational analysis of the slip behavior of the stable polymorph. This method provides the first reported non-invasive X-ray diffraction pattern quantitation of crystal forms in intact compacts.

Accelerated fluid bed drying using NIR monitoring and phenomenological modeling: method assessment and formulation suitability.

The theory behind a fluidized bed fast-drying method is investigated as a potential timesaving process, which can reduce overall drying time compared to single-temperature cycles. The method teaches that for formulations in which heat transfer dominates the drying mechanism, an increase in temperature during the evaporative phase of drying decreases overall process time by 50%, without changing the physical properties of the active ingredient. The method is also examined in terms of its potential for cycle shortening for a given formulation. A combined expression for the overall drying profile has been developed and committed to a macro that facilitates the identification of phenomenological trends, which identify whether or not a process will benefit by using fast drying. The relationship and macro also allows prediction of time frames associated with a given set of dryer and formulation parameters.