Elucidating the Impact of Material Properties on Tablet Manufacturability for Binary Paracetamol Blends.

PURPOSE: Although the mechanical properties of paracetamol and MCC are extensively described in literature, there still is a need for a better understanding of the material properties impacting them. Thus, this study systematically analyzed material properties of paracetamol-MCC blends to elucidate their influence on the mechanical tablet properties in roller compaction and direct compression with special focus on surface properties. METHODS: Multiple material characteristics of binary mixtures of paracetamol and MCC with varying drug loads were analyzed, with particular emphasis on specific surface area and surface energy. Subsequently, mechanical tablet properties of the materials in direct compression and after roller compaction were examined. RESULTS: It was demonstrated that the impact of the initial material properties on mechanical tablet properties prevailed over the impact of processing route for paracetamol-MCC blends, underlining the importance of material characterization for tabletability of oral solid dosage forms. By applying bivariate as well as multivariate analysis, key material properties influencing the tabletability of paracetamol, MCC and its mixtures such as surface area, surface energy, effective angle of internal friction and density descriptors were identified. CONCLUSIONS: This study highlighted the importance of comprehensive assessment of different material characteristics leading to a deeper understanding of underlying factors impacting mechanical tablet properties in direct compression and after roller compaction by the example of paracetamol-MCC mixtures with varying drug loads. Furthermore, it was shown that multivariate analysis could be a valuable extension to common bivariate analysis to reveal underlying correlations of material properties.

Multivariate analysis for optimization and validation of the industrial tablet-manufacturing process.

OBJECTIVE: This study aimed initially to optimize the industrial tablet-manufacturing process using multivariate analysis, and then to validate the model obtained. The study also provides a comprehensive review of the influence of different factors on relevant biopharmaceutical parameters. SIGNIFICANCE: This is the first time multivariate analysis has been applied to such a broad set of industrial data to investigate the influence of starting materials and the tablet-manufacturing processes on drug dissolution. METHODS: Partial least squares regression was retrospectively applied to the data obtained from 2 years production, to study the influence of 90 factors on dissolution of tablets that contained two active pharmaceutical ingredients. The model established was verified using the worst-case approach and process validation. RESULTS: Croscarmellose sodium had the most significant influence on drug dissolution, with the next significant factors as sodium chloride and sodium glycolate content, settling volume, particle size, suspension pH, loss on drying, and maximum temperature during drying. Loss on drying of microcrystalline cellulose and specific surface area of magnesium stearate were also essential factors. Among the process parameters, auger speed during roller compaction, compression speed, and force feeder speed during tablet compression had significant impacts on the tablet dissolution rate. The multivariate model created satisfied the process validation. CONCLUSIONS: This multivariate analysis is a useful tool to predict and optimize critical material attributes and process parameters. The variability of the materials can be successfully compensated for using various process parameters, to ensure consistent approved drug quality, to thus provide better patient care.

QbD approach to downstream processing of spray-dried amorphous solid dispersions - a case study.

In the current study, we demonstrate a structured approach to downstream process development for spray dried amorphous solid dispersions. Direct compression is generally not suitable due to typically poor flow of spray dried powders in tablets. Roller compaction (RC) is therefore the method of choice to enable spray dried dispersion downstream processing. Here, a structured experimental design of RC process parameters was used. The objective was to identify process conditions that lead to improved powder flow without compromising tablet robustness. Ten blends were compacted using different process parameters, and subsequently compressed into tablets. The impact of process parameters on granules and tablet properties was analyzed. We demonstrate that compaction force, gap and mesh aperture have major impact on RC outcomes. A combination of large gap and low force was identified as optimum combination of RC process parameters leading to powder flow improvement that could guarantee low tablet weight variation and at the same prevented loss of blend compressibility.

A Multi-variate Mathematical Model for Simulating the Granule Size Distribution in Roller Compaction-Milling Process.

Granule size distribution (GSD) is one of the critical quality attributes in the roller compaction (RC) process. Determination of GSD for newly developed pharmaceutical compounds with unknown ribbon breakage behaviors at the RC milling step requires a quantitative insight into process parameters and ribbon attributes. Despite its pivotal role in mapping the process operating conditions to achieve desired granule size, limited work has been presented in literature with a focus on RC-milling modeling. In this study, a multi-variate mathematical model is presented to simulate the full size-distribution of granulated ribbons as a function of ribbon mechanical properties. Experimental data with a lab-scale oscillating milling apparatus were generated using ribbons made of various powder compositions. Model parameters were determined by fitting it to experimental data sets. Parameters obtained from the first step were correlated to ribbon Young's modulus. The model was validated by predicting GSD of data that were excluded in model development step. Predictive capabilities of the developed model were further explored by simulating GSD profiles of a granulated pharmaceutical excipient obtained at three different conditions of a real-scale Gerteis RC system. While maintaining the milling operating conditions similar to the lab-scale apparatus (i.e., screen size and spacing, and low rotor speed), the proposed modeling approach successfully predicted the GSD of roller compacted MCC powder as the model compound. This model can be alternatively utilized in conjunction with an RC model in order to facilitate the process understanding to obtain granule attributes as part of Quality-by-Design paradigm.

Understanding the Performance of a Novel Direct Compression Excipient Comprising Roller Compacted Chitin.

Chitin has been investigated in the context of finding new excipients suitable for direct compression, when subjected to roller compaction. Ball milling was concurrently carried out to compare effects from different energy or stress-inducing techniques. Samples of chitin powders (raw, processed, dried and humidified) were compared for variations in morphology, X-ray diffraction patterns, densities, FT-IR, flowability, compressibility and compactibility. Results confirmed the suitability of roller compaction to convert the fluffy powder of raw chitin to a bulky material with improved flow. X-ray powder diffraction studies showed that, in contrast to the high decrease in crystallinity upon ball milling, roller compaction manifested a slight deformation in the crystal lattice. Moreover, the new excipient showed high resistance to compression, due to the high compactibility of the granules formed. This was correlated to the significant extent of plastic deformation compared to the raw and ball milled forms of chitin. On the other hand, drying and humidification of raw and processed materials presented no added value to the compressibility and compactibility of the directly compressed excipient. Finally, compacted chitin showed direct compression similarity with microcrystalline cellulose when formulated with metronidazole (200 mg) without affecting the immediate drug release action of the drug.

Investigation on the effect of roller compaction on paracetamol.

Roller compaction is a popular dry granulation method that has been associated with loss of tabletability. In this study, the effect of roller compaction on a model brittle elastic material, paracetamol, was examined. Roller compaction of paracetamol was carried out at three roll force to examine the effects of roll force on the tablet compaction properties. Paracetamol granules consisting of small fragmented crystals were created through the process of roller compaction. A compaction simulator was used to produce tablets from a sieved fraction of roller compacted paracetamol and non-roller compacted paracetamol. Despite the higher elastic energy to plastic energy ratio observed with tablets produced from roller compacted granules of higher forces, the table tensile strength obtained was higher with a lower capping coefficient. At the same time, tablet elastic recovery was found to be lower for tablets produced using roller compacted paracetamol granules. Prefragmentation during roller compaction process helped to reduce the energy required for fragmentation during tablet compaction, increasing the energy available for bond formation. Roller compaction of brittle elastic materials may be a viable option for improving tablet tensile strength and reducing tablet capping.

Determining the Impact of Roller Compaction Processing Conditions on Granule and API Properties.

The attrition of drug particles during the process of dry granulation, which may (or may not) be incorporated into granules, could be an important factor in determining the subsequent performance of that granulation, including key factors such as sticking to punches and bio-performance of the dosage form. It has previously been demonstrated that such attrition occurs in one common dry granulation process train; however, the fate of these comminuted particles in granules was not determined. An understanding of the phenomena of attrition and incorporation into granule will improve our ability to understand the performance of granulated systems, ultimately leading to an improvement in our ability to optimize and model the process. Unique feeding mechanisms, geometry, and milling systems of roller compaction equipment mean that attrition could be more or less substantial for any given equipment train. In this work, we examined attrition of API particles and their incorporation into granule in an equipment train from Gerteis, a commonly used equipment train for dry granulation. The results demonstrate that comminuted drug particles can exist free in post-milling blends of roller compaction equipment trains. This information can help better understand the performance of the granulations, and be incorporated into mechanistic models to optimize such processes.

Optimization of the process variables of roller compaction, on the basis of granules characteristics (flow, mechanical strength, and disintegration behavior): an application of SeDeM-ODT expert system.

The objective of the study was application of SeDeM-ODT expert system for optimization of process variables for roller compaction and for the preparation of granules with better flow, compressibility, and disintegration behavior. In the present study, granules were prepared at pre-determined (on the basis of factorial design) process variables and characterized using SeDeM-ODT expert system. Compatibility of ribavirin with excipients (microcrystalline cellulose, tablettose-80, cross carmellose sodium, and magnesium stearate) was evaluated by binary mixture approach, using FTIR. According to the SeDeM-ODT expert system, granules were characterized for various parameters related to flow, compressibility and disintegration behavior and Index of Good Compressibility and Buccodispersibility (IGCB) was calculated. The process variables resulting in highest IGCB value were considered as optimum. Ribavirin was found compatible with all the excipients used in the study and characteristics peaks were present in FTIR spectra after subjecting to stress conditions (75% relative humidity at 45 ± 5 °C) for 30 days. Both Ribavirin powder and Ribavirin containing powder blend had poor flow and compressibility while disintegration behavior was good due to higher water solubility. Screw speed of 35 rpm and roller speed at 12 rpm resulted in granules with acceptable characteristics. The IGCB value (5.63) of the granules was highest of all, indicating its better characteristics. SeDeM-ODT expert system presents a more practical picture of the granules and also predicts the mechanical strength and disintegration behavior of the tablets prepared from the granules. By proper optimization of screw and roller speed, efficiency of the process can be improved.

Parameter estimation for roller compaction process using an instrumented vector TF mini roller compactor.

Using instrumented roll technology, statistical models relating process parameters such as hydraulic pressure, roll speed and screw speed of Vector TF mini roller compactor to ribbon normal stress and density were developed for placebo blends. Normal stress was found to be directly proportional to hydraulic pressure, roll speed and inversely to screw to roll speed ratio. A power-law relationship between ribbon density and normal stress was observed for placebo blends. Models developed for placebo were found to predict ribbon densities of active blends with good accuracy. Standard optimization of roller compaction process parameters involves the investment of a large amount of time and active ingredient. These models can, therefore, be utilized to predict starting instrument settings required to generate a ribbon of desired solid fraction during early-stage development where material availability & time is limited.

Modification of α-lactose monohydrate as a direct compression excipient using roller compaction.

Roller compaction was used to prepare a direct-compressed lactose excipient using crystalline α-lactose monohydrate. The effect of various roller compaction process parameters (compaction pressure, compaction repetition, and speed ratio) on the characteristics of compacted α-lactose monohydrate was investigated. Results were compared with data obtained using industrial spray-dried lactose and lactose samples with different degrees of crystallinity. XRPD analysis revealed that roller compaction reduced the crystallinity of α-lactose monohydrate, and the resulting material is similar to spray-dried lactose in behavior as a direct compression excipient. Roller compaction introduced desirable characteristics to the raw α-lactose monohydrate by inducing changes in crystallinity and particle morphology. Scanning electron microscopy results indicated that the compaction process converted some of the original torpedo-shaped crystals of α-lactose monohydrate into a more cylindrical shape with rounded edges. Compaction pressure and repetition of compaction have a significant effect on the modification of the crystallinity of the processed, raw α-lactose monohydrate.

Tricalcium citrate - a new brittle tableting excipient for direct compression and dry granulation with enormous hardness yield.

OBJECTIVES: Tricalcium citrate (TCC) was characterized as a tableting excipient for direct compression (DC) and dry granulation (DG). SIGNIFICANCE: Brittle materials usually lead to tablets of inferior mechanical strength compared to plastic deforming materials. A brittle material exhibiting a high tabletability with the ability to retain that behavior during recompression would represent a valuable alternative to the commonly used microcrystalline cellulose. METHODS: Tablets of TCC and other common fillers were directly compressed for the purpose of compression analysis including Heckel analysis, speed dependency, and lubricant sensitivity. DG by roller compaction of TCC was first simulated via briquetting and experiments were subsequently repeated on a roller compactor. RESULTS: TCC appears as an excellent flowing powder of large agglomerates consisting of lower micron to submicron platelets. Despite the brittle deformation mechanism identified in the Heckel analysis, TCC demonstrated a very high mechanical strength up to 11 MPa in conjunction with an astonishingly low solid fraction of 0.85 at a compression pressure of 400 MPa. This was seen along with hardly any speed and lubricant sensitivity. Nevertheless, disintegration time was very short. TCC tablets suffered only a little from the re-compression: a slight loss in tensile strength of 1-2 MPa was observed for granules produced via roller compaction. CONCLUSIONS: TCC was found to be suitable for DC as a predominantly brittle deforming filler, nevertheless demonstrating an enormous hardness yield while being independent of lubrication and tableting speed. TCC furthermore retained enough bonding capacity after DG to maintain this pronounced tabletability.

Comparative binder efficiency modeling of dry granulation binders using roller compaction.

Roller compaction parameters' impact on granules and tableting properties of coprocessed Avicel® DG [ADG], a physical mixture of the two components at the same composition present in ADG [PADCP], and microcrystalline cellulose and Kollidon® VA-64 Fine physical mixture [KVA64] was quantified by analysis of variance (ANOVA) and multivariate methods. Roller force, roller gap, and roller speed levels were selected for evaluation. A 33 full-factorial experimental design with three center points for roller force, roller gap, and roller speed was used. The response parameters studied were granule-to-fines (GF) ratio, compressibility index (CI), tablet thickness (TT), tablet friability (TF), tablet breaking force (TBF) and disintegration time (DT). A model acetaminophen tablet formulation was roller granulated and tableted at 10 kg scale. Principal component analysis of ADG and PADCP formulations were separated from KVA64 formulations, indicating different granule and tableting properties were binder dependent. This difference in binder performance was also confirmed by ANOVA. The ANOVA also showed that there were no statistical performance differences between coprocessed ADG and its comparable physical blend with the exception of TT. Principal component regression (PCR) analyses of ADG and PADCP revealed that these excipients exhibited a statistically significant negative effect on granules-to-fine (GF) ratio, TT, TBF, and DT. KVA64 demonstrated a positive effect on these parameters. The KVA64 physical mixture demonstrated an overall better performance and binding capability. This study strongly suggests that there is no performance advantage of coprocessed Avicel® DG when compared to a physical mixture of the two components at the same composition.

Simultaneous Comparison of Two Roller Compaction Techniques and Two Particle Size Analysis Methods.

A new dry granulation technique, gas-assisted roller compaction (GARC), was compared with conventional roller compaction (CRC) by manufacturing 34 granulation batches. The process variables studied were roll pressure, roll speed, and sieve size of the conical mill. The main quality attributes measured were granule size and flow characteristics. Within granulations also the real applicability of two particle size analysis techniques, sieve analysis (SA) and fast imaging technique (Flashsizer, FS), was tested. All granules obtained were acceptable. In general, the particle size of GARC granules was slightly larger than that of CRC granules. In addition, the GARC granules had better flowability. For example, the tablet weight variation of GARC granules was close to 2%, indicating good flowing and packing characteristics. The comparison of the two particle size analysis techniques showed that SA was more accurate in determining wide and bimodal size distributions while FS showed narrower and mono-modal distributions. However, both techniques gave good estimates for mean granule sizes. Overall, SA was a time-consuming but accurate technique that provided reliable information for the entire granule size distribution. By contrast, FS oversimplified the shape of the size distribution, but nevertheless yielded acceptable estimates for mean particle size. In general, FS was two to three orders of magnitude faster than SA.

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.

Quality-by-Design II: Application of Quantitative Risk Analysis to the Formulation of Ciprofloxacin Tablets.

Qualitative risk assessment methods are often used as the first step to determining design space boundaries; however, quantitative assessments of risk with respect to the design space, i.e., calculating the probability of failure for a given severity, are needed to fully characterize design space boundaries. Quantitative risk assessment methods in design and operational spaces are a significant aid to evaluating proposed design space boundaries. The goal of this paper is to demonstrate a relatively simple strategy for design space definition using a simplified Bayesian Monte Carlo simulation. This paper builds on a previous paper that used failure mode and effects analysis (FMEA) qualitative risk assessment and Plackett-Burman design of experiments to identity the critical quality attributes. The results show that the sequential use of qualitative and quantitative risk assessments can focus the design of experiments on a reduced set of critical material and process parameters that determine a robust design space under conditions of limited laboratory experimentation. This approach provides a strategy by which the degree of risk associated with each known parameter can be calculated and allocates resources in a manner that manages risk to an acceptable level.

Near-infrared spectroscopic analysis of the breaking force of extended-release matrix tablets prepared by roller-compaction: influence of plasticizer levels and sintering temperature.

The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for the determination of the influence of sintering temperature and plasticizer levels on the breaking force of extended-release matrix tablets prepared via roller-compaction. Six formulations using theophylline as a model drug, Eudragit® RL PO or Eudragit® RS PO as a matrix former and three levels of TEC (triethyl citrate) as a plasticizer were prepared. The powder blend was roller compacted using a fixed roll-gap of 1.5 mm, feed screw speed to roller speed ratio of 5:1 and roll pressure of 4 MPa. The granules, after removing fines, were compacted into tablets on a Stokes B2 rotary tablet press at a compression force of 7 kN. The tablets were thermally treated at different temperatures (Room Temperature, 50, 75 and 100 °C) for 5 h. These tablets were scanned in reflectance mode in the wavelength range of 400-2500 nm and were evaluated for breaking force. Tablet breaking force significantly increased with increasing plasticizer levels and with increases in the sintering temperature. An increase in tablet hardness produced an upward shift (increase in absorbance) in the NIR spectra. The principle component analysis (PCA) of the spectra was able to distinguish samples with different plasticizer levels and sintering temperatures. In addition, a 9-factor partial least squares (PLS) regression model for tablets containing Eudragit® RL PO had an r(2) of 0.9797, a standard error of calibration of 0.6255 and a standard error of cross validation (SECV) of 0.7594. Similar analysis of tablets containing Eudragit® RS PO showed an r(2) of 0.9831, a standard error of calibration of 0.9711 and an SECV of 1.192.

Tablet formulation of an active pharmaceutical ingredient with a sticking and filming problem: direct compression and dry granulation evaluations.

OBJECTIVE: To develop a tablet formulation for an active pharmaceutical ingredient for which sticking and filming problems occurred during tablet punching. METHODS: Direct compression and dry granulation tableting techniques were evaluated using factorial experimental design. The effects of chrome-coated punch tips, filler types and active percent in the tablet formulation by direct compression were evaluated. Similarly, for dry granulation using the roller compaction technique, three formulation factors - roller compaction pressure, intragranular filler percent and filler type - were studied. Tablets prepared by both techniques were characterized in regard to their compressibility index, tablet hardness, disintegration time, friability index and stickiness-filming index (an arbitrary index). Ten formulations were prepared by each technique. Using multiple response optimizations and estimated response surface plots, the data were analyzed to identify optimum levels for the formulation factors. RESULTS: Compressibility index values for all the formulations prepared by direct compression exceeded 25%, unlike the blends prepared by dry granulation. Both tablet hardness and disintegration time for direct compression formulations were significantly lower than for dry granulation formulations. The friability index values were significantly higher for direct compression formulations than for dry granulation formulations. All the direct compression formulations, unlike the dry granulation formulations, had a high stickiness-filming index. CONCLUSION: Statistical analysis helped in identifying the optimum levels of formulation factors, as well as the method for eliminating sticking and filming. Unlike the direct compression technique, dry granulation yielded tablets for which sticking and filming were completely eliminated.

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.

Modified Roller Compaction Model to Account for Roll Speed Effect on Powder Compaction in Dry Granulation Process.

This study introduces a modification to the roller compaction model proposed by Sousa et al.1 to account for the effect of roll speed on powder compaction in the dry granulation process. The proposed model enhances the prediction accuracy, particularly at higher roll speeds, which are often overlooked in existing models. The modified model is validated using literature data, demonstrating improved performance compared to the original model. Additionally, the model is applied to a pharmaceutical formulation, showing its applicability in an industrial context. The integration of the model into gPROMS allows for global sensitivity analysis and design space exploration, providing valuable insights for process optimization and scale-up. The study contributes to the understanding of roller compaction dynamics and offers a practical tool for decision-making in pharmaceutical manufacturing.

The impacts of roller compaction on the quality attributes of simultaneously compressed micro and minitablets.

The challenges of developing good quality low dose minitablets was assessed by systematically studying the effects of ibuprofen (IBU, a model compound) particle sizes (6-58 µm D50) and concentrations (0.1-3 %w/w), roller compaction forces (3-7 kN/cm), and the minitablet sizes (1.2, 1.5 and 2 mm diameter). A novel compression approach, where all three minitablet sizes were simultaneously produced in a single compression run was used. Roller compacted ribbons, granules, minitablets were characterized for physico-mechanical properties and minitablets were also characterized for stratified content uniformity and weight uniformity. The results showed that roll force was the more dominant factor to ribbon solid fraction or tensile strength and granule size enlargement. Minitablets obtained from the granules had good weight uniformity; all but one batch met the criteria. The precise control of tooling lengths across the various sizes was found profoundly important for achieving expected weights, solid fraction, and tensile strength of the simultaneously produced minitablets. The roller compaction process considerably improved the CU variability of the minitablets as compared to the direct compression process. Smaller particle size and higher concentration of IBU, increased roller compaction force, and larger minitablet size improved the potency and content uniformity; however, only the minitablet size was a statistically significant factor in this study. As a product strategic design criterion, a threshold of 25 minitablets in a dosage unit would ensure robust downstream filling and weight verification operations as well as dose accuracy and uniformity (would pass stage 1 criteria). This study results demonstrated feasibility of the novel simultaneous compression approach and the roller compaction process in developing good quality minitablets.