Using a Model-based Material Sparing Approach for Formulation and Process Development of a Roller Compacted Drug Product.

The present work details a material sparing approach that combines material profiling with Instron uniaxial die-punch tester and use of a roller compaction mathematical model to guide both formulation and process development of a roller-compacted drug product. True density, compression profiling, and frictional properties of the pre-blend powders are used as inputs for the predictive roller compaction model, while flow properties, particle size distribution, and assay uniformity of roller compaction granules are used to select formulation composition and ribbon solid fraction. Using less than 10 g of a model drug compound for material profiling, roller compacted blend in capsule formulations with appropriate excipient ratios were developed at both 1.4% and 14.4% drug loadings. Subsequently, scale-up batches were successfully manufactured based on the roller compaction process parameters obtained from predictive modeling. The measured solid fractions of roller compaction ribbon samples from the scale-up batches were in good agreement with the target solid fraction of the modeling. This approach demonstrated considerable advantages through savings in both materials and number of batches in the development of a roller-compacted drug product, which is of particular value at early development stages when drug substance is often limited and timelines are aggressive.

Particle Property Characterization and Data Curation for Effective Powder Property Modeling in the Pharmaceutical Industry.

Computational modeling, machine learning, and statistical data analysis are increasingly utilized to mitigate chemistry, manufacturing, and control failures related to particle properties in solid dosage form manufacture. Advances in particle characterization techniques and computational approaches provide unprecedented opportunities to explore relationships between particle morphology and drug product manufacturability. Achieving this, however, has numerous challenges such as producing and appropriately curating robust particle size and shape data. Addressing these challenges requires a harmonized strategy from material sampling practices, characterization technique selection, and data curation to provide data sets which are informative on material properties. Herein, common sources of error in particle characterization and data compression are reviewed, and a proposal for providing robust particle morphology (size and shape) data to support modeling efforts, approaches for data curation, and the outlook for modeling particle properties are discussed.

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.

Morphological distribution mapping: Utilisation of modelling to integrate particle size and shape distributions.

The aim of this work was to develop approaches to utilize whole particle distributions for both particle size and particle shape parameters to map the full range of particle properties in a curated dataset. It is hoped that such an approach may enable a more complete understanding of the particle landscape as a step towards improving the link between particle properties and processing behaviour. A 1-dimensional principal component analysis (PCA) approach was applied to create a 'morphological distribution landscape'. A dataset of imaged APIs, intermediates and excipients encompassing particle size, particle shape (elongation, length and width) and distribution shape was curated between 2008 and 2022. The curated dataset encompassed over 200 different materials, which included over 150 different APIs, and approximately 3500 unique samples. For the purposes of the current work, only API samples were included. The morphological landscape enables differentiation of materials of equivalent size but varying shape and vice versa. It is hoped that this type of approach can be utilised to better understand the influence of particle properties on pharmaceutical processing behaviour and thereby enable scientists to leverage historical knowledge to highlight and mitigate risks associated to materials of similar morphological nature.

A quantitative correlation of the effect of density distributions in roller-compacted ribbons on the mechanical properties of tablets using ultrasonics and X-ray tomography.

Enabling the paradigm of quality by design requires the ability to quantitatively correlate material properties and process variables to measureable product performance attributes. In this study, we show how heterogeneities in compacted ribbon densities quantitatively correlate to tablet mechanical properties. These density variations, which have been purposely modulated by internal and external lubrications, are characterized longitudinally and transversally by nondestructive ultrasonic and X-ray micro-computed tomography measurements. Subsequently, different transversal regions of the compacted ribbon are milled under the same conditions, and granules with nominally the same particle size distribution are utilized to manufacture cylindrical tablets, whose mechanical properties are further analyzed by ultrasonic measurements. We consider three different ribbon conditions: no lubrication (case 1); lubricated powder (case 2); and lubricated tooling (hopper, side sealing plates, feed screws, and rolls) (case 3). This study quantitatively reveals that variation in local densities in ribbons (for case 1) and process conditions (i.e., internal case 2 and external lubrication case 3) during roller compaction significantly affect the mechanical properties of tablets even for granules with the same particle size distribution. For case 1, the mechanical properties of tablets depend on the spatial location where granules are produced. For cases 2 and 3, the ribbon density homogeneity was improved by the use of a lubricant. It is demonstrated that the mechanical performances of tablets are decreased due to applied lubricant and work-hardening phenomenon. Moreover, we extended our study to correlate the speed of sound to the tensile strength of the tablet. It is found that the speed of sound increases with the tensile strength for the tested tablets.

Data-smart machine learning methods for predicting composition-dependent Young's modulus of pharmaceutical compacts.

The ability to predict mechanical properties of compacted powder blends of Active Pharmaceutical Ingredients (API) and excipients solely from component properties can reduce the amount of 'trial-and-error' involved in formulation design. Machine Learning (ML) can reduce model development time and effort with the imperative of adequate historical data. This work describes the utility of linear and nonlinear ML models for predicting Young's modulus (YM) of directly compressed blends of known excipients and unknown API mixed at arbitrary compositions given only the true density of the API. The models were trained with data from compacts of three BCS Class I APIs and two excipients blended at four drug loadings, three excipient compositions, and compacted to five nominal solid fractions. The prediction accuracy of the models was measured using three cross-validation (CV) schemes. Finally, we demonstrate an application of the model to enable Quality-by-Design in formulation design. Limitations of the models and future work have also been discussed.

Mechanical property characterization of bilayered tablets using nondestructive air-coupled acoustics.

A noncontact/nondestructive air-coupled acoustic technique to be potentially used in mechanical property determination of bilayer tablets is presented. In the reported experiments, a bilayer tablet is vibrated via an acoustic field of an air-coupled transducer in a frequency range sufficiently high to excite several vibrational modes (harmonics) of the tablet. The tablet vibrational transient responses at a number of measurement points on the tablet are acquired by a laser vibrometer in a noncontact manner. An iterative computational procedure based on the finite element method is utilized to extract the Young's modulus, the Poisson's ratio, and the mass density values of each layer material of a bilayer tablet from a subset of the measured resonance frequencies. For verification purposes, a contact ultrasonic technique based on the time-of-flight data of the longitudinal (pressure) and transverse (shear) acoustic waves in each layer of a bilayer tablet is also utilized. The extracted mechanical properties from the air-coupled acoustic data agree well with those determined from the contact ultrasonic measurements. The mechanical properties of solid oral dosage forms have been shown to impact its mechanical integrity, disintegration profile and the release rate of the drug in the digestive tract, thus potentially affecting its therapeutic response. The presented nondestructive technique provides greater insight into the mechanical properties of the bilayer tablets and has the potential to identify quality and performance problems related to the mechanical properties of the bilayer tablets early on the production process and, consequently, reduce associated cost and material waste.

Reproducibility of the Measurement of Bulk/Tapped Density of Pharmaceutical Powders Between Pharmaceutical Laboratories.

The bulk properties of a powder are dependent on the preparation, treatment, and storage of the sample, that is, how it was handled. The particles can be packed to have a range of bulk densities and, moreover, the slightest disturbance of the powder bed may result in a changed bulk density. Thus, the bulk density of a powder is often difficult to measure with good reproducibility and, in reporting the results, it is essential to specify how the determination was made. In this article, we measured the bulk density, tapped density, and calculated the Hausner ratio of commonly used excipients with similar tapped density testers and followed the United States Pharmacopeia 30-National Formulary 25-S1 testing procedure. Based on the analysis, within lot and lot-to-lot variability and the relative errors for bulk density, tapped density, and Hausner ratio were found to be acceptable. Lot-to-lot differences were generally not measurable using this test as they were found to be within the variability of the test. The results also indicated that there was no statistically significant bias between sites for tapped density and Hausner ratio, but there was a marginally significant bias in the bulk density data set.

Air-coupled non-contact mechanical property determination of drug tablets.

A non-contact/non-destructive technique for determining the mechanical properties of coated drug tablets is presented. In the current measurement approach, air-coupled excitation and laser interferometric detection are utilized and their effectiveness in characterizing the mechanical properties of a drug tablet by examining its vibrational resonance frequencies is demonstrated. The drug tablet is vibrated via an acoustic field of an air-coupled transducer in a frequency range sufficiently high to excite its several vibrational modes (harmonics). The tablet surface vibrational responses at measurement points are acquired by a laser vibrometer in a non-contact manner. An iterative computational procedure based on the finite element method is developed to extract the mechanical properties of the coated tablet from a subset of its measured resonance frequencies. The mechanical properties measured by this technique are compared to those obtained by a standard contact ultrasonic measurement method and a good agreement is found. Sensitivities of the resonance frequencies to the changes in the tablet mechanical properties are also obtained and discussed. The presented non-destructive technique requires no physical contact with the tablet and operates in the microsecond time-scale. Therefore, it could be employed for rapid monitoring and characterization applications.

Drug tablet thickness estimations using air-coupled acoustics.

A non-contact/non-destructive acoustic technique for predicting the coating layer thickness of a drug tablet is presented. Quality of tablet coatings can play a major role in the effectiveness of drug delivery. Many pharmaceutical tablets consist of a tablet core and a coated outer cover. Variations in the tablet coating can be indicative of various process problems and, therefore, is of a concern for quality assurance. In the current non-contact measurement system, an air-coupled excitation and laser interferometric detection for predicting the coating layer thickness of a drug tablet is introduced. Drug tablets with different coating thicknesses are vibrated via an acoustic field generated by an air-coupled transducer in a frequency range sufficiently high to excite their several vibrational modes. The tablet surface vibrational responses are acquired at a number of measurement points by a laser interferometer in a non-contact manner. An iterative computational procedure, based on the FE method and Newton's method, was developed and demonstrated to extract the coating layer thicknesses of the tablets from a subset of the measured resonance frequencies.

Non-destructive acoustic defect detection in drug tablets.

For physical defect detection in drug tablets, a non-destructive and non-contact technique based on air coupled excitation and interferometric detection is presented. Physical properties and mechanical integrity of drug tablets can often affect their therapeutic and structural functions. The monitoring for defects and the characterization of tablet mechanical properties therefore have been of practical interest for solid oral dosage forms. The presented monitoring approach is based on the analysis of the transient vibrational responses of an acoustically excited tablet in both in temporal and spectral domains. The pulsed acoustic field exciting the tablet is generated by an air-coupled transducer. Using a laser vibrometer, the out-of-plane vibrational transient response of the tablet is detected and acquired in a non-contact manner. The physical state of the tablet is evaluated based on the spectral properties of these transient responses. In the current study, the effectiveness of three types of simple similarity measures is evaluated for their potential uses as defect detection norms, and for their potential use in quantifying the extent of tablet defect is discussed. It is found that these quantities can not only be used for identification of defective tablets, but could also provide a measure for the extent of the damage.

A Practical Framework Toward Prediction of Breaking Force and Disintegration of Tablet Formulations Using Machine Learning Tools.

Enabling the paradigm of quality by design requires the ability to quantitatively correlate material properties and process variables to measureable product performance attributes. Conventional, quality-by-test methods for determining tablet breaking force and disintegration time usually involve destructive tests, which consume significant amount of time and labor and provide limited information. Recent advances in material characterization, statistical analysis, and machine learning have provided multiple tools that have the potential to develop nondestructive, fast, and accurate approaches in drug product development. In this work, a methodology to predict the breaking force and disintegration time of tablet formulations using nondestructive ultrasonics and machine learning tools was developed. The input variables to the model include intrinsic properties of formulation and extrinsic process variables influencing the tablet during manufacturing. The model has been applied to predict breaking force and disintegration time using small quantities of active pharmaceutical ingredient and prototype formulation designs. The novel approach presented is a step forward toward rational design of a robust drug product based on insight into the performance of common materials during formulation and process development. It may also help expedite drug product development timeline and reduce active pharmaceutical ingredient usage while improving efficiency of the overall process.

Quantitative correlation of the effect of process conditions on the capping tendencies of tablet formulations.

Capping is a mechanical defect in tablet formulation and manufacture. Understanding what influences tablet capping in terms of process variables and formulation properties and developing specialized techniques to correlate these variables with mechanical failures are practical interests of the pharmaceutical industry. Tablet compression emulator was used to rank order capping tendencies of a diverse sample set. The compression forces of 5-25 kN were used to compress round, beveled edge, and oval shape tablets. Compression speeds of 25, 40, and 80 rpm were chosen as representative ranges for bench-to-manufacturing-scale processing. Tablets were tested by in-house developed nondestructive ultrasonic method. The measurements revealed that elastic modulus vary with different testing orientations that indicated elastic modulus anisotropy in tablets. It was shown that altering process conditions such as tooling, compression force, and compression speed significantly impact the capping tendencies of formulations. A systematic approach has been applied to develop a predictive tool to assess capping tendencies of formulations. The developed tool is fast, material sparing, and has potential to flag the risk of manufacturability issues and provide insight into the performance of formulations during early development.

Review of bilayer tablet technology.

Therapeutic strategies based on oral delivery of bilayer (and multilayer) tablets are gaining more acceptance among brand and generic products due to a confluence of factors including advanced delivery strategies, patient compliance and combination therapy. Successful manufacturing of these ever more complex systems needs to overcome a series of challenges from formulation design to tablet press monitoring and control. This article provides an overview of the state-of-the-art of bilayer tablet technology, highlighting the main benefits of this type of oral dosage forms while providing a description of current challenges and advances toward improving manufacturing practices and product quality. Several aspects relevant to bilayer tablet manufacturing are addressed including material properties, lubrication, layer ordering, layer thickness, layer weight control, as well as first and final compression forces. A section is also devoted to bilayer tablet characterization that present additional complexities associated with interfaces between layers. The available features of the manufacturing equipment for bilayer tablet production are also described indicating the different strategies for sensing and controls offered by bilayer tablet press manufacturers. Finally, a roadmap for bilayer tablet manufacturing is advanced as a guideline to formulation design and selection of process parameters and equipment.

Influence of compaction properties and interfacial topography on the performance of bilayer tablets.

Bilayer tablets are generating great interest recently as they can achieve controlled delivery of different drugs with pre-defined release profiles. However, the production of such tablets has been facing great challenges as the layered tablets are prone to delaminate or fracture in the individual layers due to insufficient bonding strength of layers and adhesion at the interfaces. This paper will provide an insight into the role of interfacial topography on the performance of the bilayer tablets. In this study, two widely used pharmaceutical excipients: microcrystalline cellulose and lactose were investigated. Bilayer tablets were manufactured with a range of first and second layer compression forces. A crack of known dimensions was introduced at the interface to investigate the crack propagation mechanisms upon axially loading the bilayer tablet, and to determine the stress intensity factor (K(I)) of the interface (will be discussed in a separate paper). The results indicated that a strong dependency of the strength of bilayer tablets and mode of crack propagation on the material and compaction properties. The results showed that the strength of bilayer tablets increased with the increase of interfacial roughness, and the first layer and second layer forces determined the magnitude of interfacial roughness for both plastic and brittle materials. Further, the results also indicated that layer sequence and compaction forces played a key role in influencing the strength of the bilayer tablets. For the same (first and second layer) force combination, interfacial strength is higher for the tablets made of brittle material in the first layer. It was observed that interfacial strength decreased with the increase of lubricant concentration. The studies showed that the effect of lubricant (i.e. reduction in compact strength with the increase of lubricant concentration) on the strength of compacts is higher for tablets made of plastic material as compared to the tablets made of brittle material.

Ultrasonic determination of Young's moduli of the coat and core materials of a drug tablet.

Many modern tablet presses have system controls that monitor the force exerted to compress the solid oral dosage forms; however this data provides only limited information about the mechanical state of the tablet due to various process and materials uncertainties. A contact pulse/echo ultrasonic scheme is presented for the determination of the local Young's moduli of the coat and the core materials of enteric-coated and monolayer coated tablets. The Young's modulus of a material compacted into solid dosage can be related to its mechanical hardness and, consequently, its dissolution rate. In the current approach, short ultrasonic pulses are generated by the active element of a delay line transducer and are launched into the tablet. The waveforms reflected from the tablet coat-core interface are captured by the same transducer and are processed for determining the reflection and transmission coefficients of the interface from partially overlapping echoes. The Young's moduli of the coat and the core materials are then extracted from these coefficients. The results are compared to those obtained by an air-coupled acoustic excitation study, and good agreement is found. The described measurement technique provides greater insight into the local physical properties of the solid oral dosage form and, as a result, has the potential to provide better hardness-related performance predictability of compacts.