Search

The purpose of the study is to present the finite difference method (FDM) and demonstrate its utility in modeling mass transport processes that are pharmaceutically relevant. In particular, diffusion processes are ideally suited for FDM because the governing equation, Fick's second law of diffusion, can be readily solved using FDM over a finite space and time. The method entails the mesh creation, space and time discretization, and solving Fick's second law at each node using finite difference-based numerical schemes. We applied FDM to study tablet disintegration, in which the tablet water uptake was simulated with an effective water diffusion coefficient; the tablet disintegration was controlled by a designated critical water content parameter, beyond which the node is treated as being disintegrated from the tablet. The resulting simulation agreed with the experimental tablet disintegration behaviors, under both disintegration-controlled and water uptake-controlled conditions. This study highlighted the unique advantage of FDM, capable of providing spatial-temporal information on water uptake and evolution of tablet size and shape during tablet disintegration, which was otherwise not available using other methods. The FDM method enabled more in-depth tablet disintegration studies. The model also has the potential to be calibrated and incorporated in tablet formulation DoE studies.

Solubility enhancement has become a common requirement for formulation development to deliver poorly water soluble drugs. Amorphous solid dispersions (ASDs) and salt formation have been two successful strategies, yet there are opportunities for further development. For ASDs, drug-polymer phase separation may occur at high drug loadings during dissolution, limiting the increase of drug loadings in ASD formulations. For salt formation, a salt form with high crystallinity and sufficient solid-state stability is required for solid dosage form development. This work studied the effect of counterions on the dissolution performance of ASDs. Surface area normalized dissolution or intrinsic dissolution methodology was employed to eliminate the effect of particle size and provide a quantitative comparison of the counterion effect on the intrinsic dissolution rate. Using indomethacin (IMC)-poly(vinylpyrrolidone-co-vinyl acetate) ASD as a model system, the effect of different bases incorporated into the ASD during preparation, the molar ratios between the base and IMC, and the drug loadings in the ASD were systematically studied. Strong bases capable of ionizing IMC significantly enhanced drug dissolution, while a weak base did not. A physical mixture of a strong base and the ASD also enhanced the dissolution rate, but the effect was less pronounced. At different base to IMC molar ratios, dissolution enhancement increased with the base to IMC ratio. At different drug loadings, without a base, the IMC dissolution rate decreased with the increase of drug loading. After incorporating a strong base, it increased with the increase of drug loading. The observations from this study were thought to be related to both the ionization of IMC in ASDs and the increase of microenvironment pH by the incorporated bases. With the significant enhancement of the drug dissolution rate, our work provides a promising approach of overcoming the dissolution limitation of ASD formulations at high drug loadings.

In tablet manufacturing, mixing operations in tumble blending (TB) and in the feed frame (FF) of the rotary press can both increase lubricity, negatively influencing the tablet mechanical strength. While the TB-driven lubrication was systematically studied, no reliable bench-scale methods exist for the effect of FF lubrication. Because TB and FF mixing are usually two successive operations in tablet manufacturing, we developed a phenomenological model to incorporate the impact of TB-driven lubrication and the FF lubrication on the tablet tensile strength (TS). We noted that exponential decay functions can describe the evolution of the tablet TS as the function of the extent of TB, as well as the residence time in FF. Hence, the overall lubrication sensitivity can be modeled by incorporating two distinct exponential decay functions. The model can be calibrated through bench-scale experiments. Using an investigational powder blend, we showed that this approach accurately predicted the tablet TS in a scale-up tablet compression study, thereby verifying its utility. This model can serve as a scale-up diagnostic and risk-assessment tool, with the ability to adjust the overall effect of lubrication by changing the TB scale and the FF residence time commensurate with the large-scale operations.

In this study, we evaluated the aerodynamic performance, dissolution, and permeation behavior of micronized fluticasone propionate (FP) and magnesium stearate (MgSt) binary mixtures. Micronized FP was dry mixed with 2% w/w MgSt using a tumble mixer and a resonant acoustic mixer (RAM) with and without heating. The mixing efficacy was determined by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analysis. Additional techniques were used to determine powder properties such as the dynamic vapor sorption (DVS), particle size distribution (PSD) by laser diffraction light scattering, and particle surface properties by scanning electron microscope (SEM). The aerodynamic performance was studied by the next-generation impactor (NGI) using drug-loaded capsules in a PlastiApi® device. Physiochemical properties such as porosity, particle size distribution, and surface area of the formulations were studied with adsorption and desorption curves fitted to several well-known models including Brunauer-Emmett-Teller (BET), Barret Joyner Halenda (BJH), and the density functional theory (DFT). The dissolution behavior of the formulations collected on the transwell inserts incorporated into stages 3, 5, and 7 of the NGI with a membrane providing an air interface was evaluated. Drug permeability of formulations was assessed by directly depositing particles on Calu-3 cells at the air-liquid interface (ALI). Drug concentration was determined by LC-MS/MS. A better MgSt mixing on micronized FP particles was achieved by mixing with a RAM with and without heating than with a tumble mixer. A significant concomitant increase in the % of emitted dose and powder aerosol performance was observed after MgSt mixing. Formulation 4 (RAM mixing at room temperature) showed the highest rate of permeability and correlation with dissolution profile. The results show that the surface enrichment of hydrophobic MgSt improved aerosolization properties and the dissolution and permeability rate of micronized FP by reducing powder agglomerations. A simple low-shear acoustic dry powder mixing method was found to be efficient and substantially improved the powder aerosolization properties and enhanced dissolution and permeability rate.

Micronization of crystalline active pharmaceutical ingredients can lead to formation of a thermodynamically unstable material with surface disorder. This material undergoes structural stabilization and particle-level changes over time that, in turn, alters the surface properties and interparticle interactions of the micronized drug. The unstable nature of the micronized drug can lead to variability in the performance of dry powder inhaler drug products. To improve the physicochemical stability of the micronized drug, an annealing step is often introduced. However, there is limited understanding of changes in the micronized drug under different annealing conditions. In this study, we examine the molecular- and particle-level changes occurring in a micronized drug during annealing under varying temperature and humidity conditions using orthogonal techniques. We demonstrate the use of surface free energy (SFE) measured by inverse gas chromatography (IGC) to monitor surface-specific changes. Micronization led to an increase in SFE, which progressively reduced during annealing. SFE trends correlated with the molecular-level surface disorder patterns measured by relative humidity perfusion microcalorimetry. The interparticle interactions tracked using IGC and atomic force microscopy show that as the micronized drug stabilized, there was a transition from dominant drug-drug cohesive forces to drug-lactose adhesive forces. For the nonhygroscopic model compound, combined high temperature-high humidity conditions showed fastest annealing kinetics. Further, the SFE descriptor enabled us to differentiate the extent of mechanical activation of the neat micronized drug and co-micronized drug-magnesium stearate blends. The study identifies tools for characterizing postmicronization material changes that can help develop materials with consistent quality.

Solubilization of new chemical entities for toxicity assessment must use excipients that do not negatively impact drug pharmacokinetics and toxicology. In this study, we investigated the tolerability of a model freebase compound, GDC-0152, solubilized by pH adjustment with succinic acid and complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) to enable intravenous use. Solubility, critical micelle concentration, and association constant with HP-β-CD were determined. Blood compatibility and potential for hemolysis were assessed in vitro. Local tolerability was assessed after intravenous and subcutaneous injections in rats. A pharmacokinetic study was conducted in rats after intravenous bolus administration. GDC-0152 exhibited pH-dependent solubility that was influenced by self-association. The presence of succinic acid increased solubility in a concentration-dependent manner. HP-β-CD alone also increased solubility, but the extent of solubility enhancement was significantly lower than succinic acid alone. Inclusion of HP-β-CD in the solution of GDC-0152 improved blood compatibility, reduced hemolytic potential by ∼20-fold in vitro, and increased the maximum tolerated dose to 80 mg/kg.

High drug load inhalable particles were prepared by co-spray drying a hydrophobic, crystalline, small molecule drug with various lipid or phospholipid excipients at a 9:1 molar ratio to understand the primary drivers of aerosol performance. The effect of excipient structure on solid-state, surface characteristics, and aerodynamic performance of the co-spray dried particles was studied while keeping the spray drying parameters constant. Spray drying of the drug with lipids produced crystalline drug particles, whereas phospholipids produced partially amorphous drug particles. All of the co-spray dried particles were nearly spherical with a smooth surface, except for the spray dried drug particles without excipients – which showed the presence of rough crystals on the surface. All co-spray dried particles showed surface enrichment of the excipient. The surface enrichment of the phospholipids was higher compared to the lipids. Co-spray dried particles that showed higher surface enrichment of excipients showed improved aerosol performance. In comparing all the excipients studied, distearyolphosphatidylcholine (DSPC) showed maximum enrichment on the particle surface and thereby significantly improved aerosol performance. This study demonstrated that the addition of small amounts of lipid excipients during spray drying can change surface morphology, composition, and cohesion, impacting aerosol performance of drugs.

The purpose of the study is to build a "virtual roller compactor" as a predictive tool to assess the roll force (RF)-maximum pressure (Pmax) and RF-ribbon density relationship for pharmaceutical roller compaction. We provided a theoretical basis to demonstrate that, there exists a critical nip angle for a pharmaceutical powder, beyond which the RF-Pmax relationship is insensitive to wall friction angle or effective angle of internal friction. We showed that for most pharmaceutical roller compaction, the critical nip angle is lower than 17 degree, and can be exceeded via wall friction elevation, using rolls with non-smooth surface. Under this condition, the original Johanson model can be substantially simplified to a single equation requiring only one material property (compressibility). By performing manufacturing-scale roller compaction using materials with diverse compressibility, we showed that the simplified, friction angle-free model performed similar to the original Johanson model. It can predict the RF-Pmax and RF-ribbon density relationship well after applying a correction factor. The predictive tool, in the form of a user-friendly graphical user interface, was created based on the simplified model. The tool was adopted for in-house, bench-scale formulation development and scale-up because of its ease-of-use, good predicting capability, and very low material demand.

The purpose of this study is to assess the prevalence of funnel flow pattern for common pharmaceutical powder blends, upon discharging from modern intermediate bulk containers (IBCs) in drug product manufacturing. The estimation was built upon Jenike’s original radial stress field theory. It was modified to account for the stress-dependence of wall friction angle commonly observed in pharmaceutical powders. A total of 260 flow pattern estimations, based on 20 real-life IBCs and 13 investigational powder blends, were made. The estimated results showed that the mass flow pattern is present in less than 5% of all cases. Funnel flow pattern is clearly prevalent among pharmaceutical powder blends. The prevalence of funnel flow stems from several factors: 1) relatively shallow hopper section shared by all IBCs, 2) the common transition-type geometry, leading to even shallower hopper inclination at the edge of the hopper section, and 3) relatively high wall friction angles resulting from low wall normal stresses. This conclusion was verified through at-scale experiments, by discharging multiple pharmaceutical powder blends from a representative IBC. In general, our study suggests that, unless the powder wall friction can be substantially reduced, pharmaceutical powders are likely to discharge under funnel flow from modern IBCs.

Anisotropic features with other crystallographic properties like d-spacing, and attachment energy (Eatt) can predict material performance during the secondary pharmaceutical processing. A newly developed state-of-the-art compression cell lodged in a powder X-ray diffractometer was used to measure anisotropic Young’s moduli (YM) of flufenamic acid (FFA) polymorphs in this study. Methodology is based on the generation of a single crystal deformation in this cell, which reflects as a change in the d-spacing in the PXRD pattern. Anisotropic YM was calculated from such information gathered along different FFA planes. Measured FFA crystallographic molecular features were concatenated to understand macroscopic compaction (Heckel and Shapirao’s parameters) and tableting performance. Block shaped crystals of FFA form I, and III after initial characterization with SEM, DSC, PXRD, and FTIR were compressed normal to X, Y, and Z-planes, identified from calculated PXRD pattern using the reported single crystal structure. YM of X and Y planes of form I was significantly higher than corresponding planes of form III. Z plane of form III showed significantly higher YM than that for form I. Low YM of form III can be attributed to its large d-spacing regardless of their high Eatt than form I, as well as orientation of supramolecular acid dimer (O H⋯O) homosynthon chains in the FFA planes. FFA form I stiffness was further confirmed with lower densification and higher yield pressure of deformation than form III. Clearly, form III exhibited better compressibility, compactibility, and tableting performance than form I due to favorable molecular and macroscopic features. Thus, developed anisotropic measurement approach can be used to distinguish material performance in the early development stage of the pharmaceutical processes.

High concentration protein solutions are generally produced by spin column concentration (SCC) during early development and by tangential flow filtration (TFF) during later stages, when greater quantities of protein become available. This is based on the assumption that the protein generated by the SCC process would be fairly similar to the TFF process material. In this study, we report the case of high concentration solutions of an Fc fusion protein produced by the two processes using the same upstream drug substance (DS) with very different storage stability. The TFF and SCC batches were characterized for aggregation, viscosity, and hydrodynamic radius before and after storage at different temperatures (5°C, 25 °C, and 40 °C). Aggregation and viscosity of the solutions processed by TFF were higher than those processed by SCC upon storage at 25 °C and 40 °C for three months. Differential scanning fluorimetry (DSF) revealed differences in initial protein conformation. Upon exposure to shear stress, protein solutions showed conformational instability and increased aggregation upon storage at 35 °C. In addition, protein solution showed higher aggregation upon shearing under mixed (downstream purification process and final formulation) buffer conditions – which are more likely to be encountered during the TFF, but not SCC, process. These results were further confirmed in an independent experiment by Fourier transform-infrared (FT-IR) spectroscopy and aggregation analysis. Taken together, these data indicate that shearing the protein in intermediate, unstable buffer conditions can lead to conformational perturbation during TFF processing, which led to higher rate of aggregation and viscosity upon storage. This study highlights the importance of testing shear stress sensitivity in the transitional buffer states of the TFF process early in development to de-risk process related product instability.

Reactive impurities in excipients can cause drug product degradation or protein modification even at trace levels, and thus impact drug stability and quality. It is critical to understand the potential impact of these impurities during development in order to ensure a robust clinical and commercial product. In this article, we review reactive impurities in pharmaceutical and biopharmaceutical excipients for both small molecule and large molecule drugs. The common reactive impurities in excipients, including peroxides, aldehydes, organic acids, reducing sugars and elemental impurities are reviewed. Sources of these impurities, reactions and impact, analytical methods, and control and risk mitigation strategies are also discussed.

Variability in oral absorption in pre-clinical species makes human dose projection challenging. In this study, we investigated the mechanistic basis of variability in oral absorption of a model hydrophobic compound with pH-dependent solubility, BMS-955829, after oral dosing in rats, dogs, and cynomolgus monkeys. The contribution of regional absorption to pharmacokinetic variability was assessed in ported monkeys by direct intraduodenal and intraileal administration. The effect of BMS-955829 on gastric emptying and intestinal motility was investigated by radiography after co-administration of barium. BMS-955829 exhibited species dependent oral bioavailability, with high variability in monkeys. During regional absorption studies, highest rate of drug absorption was observed after direct intraduodenal administration. Radiography studies indicated that BMS-955829 slowed gastric emptying and intestinal motility. The effect of rate and site of drug release on oral exposure was studied using different drug product formulations. Reducing the rate of drug release reduced oral exposure variability without compromising exposure in cynomolgus monkeys. This effect was likely mediated by avoidance of rapid initial absorption and drug effect on gastric emptying and intestinal transit within the biorelevant timeframe. Thus, drug release rate can modulate the effect of physiological factors on variability in the oral absorption of sensitive compounds.

Application of in-line real-time process monitoring using a process analytical technology for granule size distribution can enable quality-by-design development of a drug product and enable attribute-based monitoring and control strategies. In this study, an in-line laser focused beam reflectance measurement (FBRM) C35 probe was used to investigate the effect of formulation and process parameters on the granule growth profile over time during the high shear wet granulation of a high drug load formulation of brivanib alaninate. The probe quantitatively captured changes in the granule chord length distribution (CLD) with the progress of granulation and delineated the impact of water concentration used during granulation. The results correlated well with offline particle size distribution measured by nested sieve analyses. An end point indication algorithm was developed that was able to successfully track the process time needed to reach the target CLD. Testing of the brivanib alaninate granulation through 25-fold scale-up of the batch process indicated that the FBRM CLD profile can provide a scale-independent granule attribute-based process fingerprint. These studies highlight the ability of FBRM to quantitate a granule attribute of interest during wet granulation that can be used as an attribute-based scale-up and process monitoring and control parameter.

Multiple pharmaceutical powder processes operate at stresses lower than utilized in typical lab-scale shear cell testing. To bridge this gap, we developed a method to determine intrinsic powder flow properties, in particular, flow function (FFc), under such low stresses. A simple, commercially-available flow-through-orifice device (Flodex™ apparatus) was selected. By developing a theoretical framework using Jenike’s radial stress field analysis, the major principal stress and FFc of the tested powder can be derived from the otherwise empirical “Flodex” experiment. This method was applied to 10 distinct pharmaceutical powders. The major principal stresses associated with the test were estimated to be in the order of 100 Pa, significantly lower than what is achievable using shear cell-based methods. The resulting FFc values are generally consistent with the data extrapolated from ring shear testing. We showed that for pharmaceutical powders, FFc decreases with decreasing consolidation stress, but the values are always greater than 1. Therefore, the threshold for poor/acceptable flowability (by FFc) should be used with caution at low-stress conditions. Through this work, we showed that by integrating the radial stress field theory with a simple flow-through-orifice experiment, intrinsic powder flow properties under low stresses could be reliably determined.

To describe a stepwise approach to evaluate the pH effect for a weakly basic drug by in vitro, in vivo and in silico techniques and identify a viable mitigation strategy that addresses the risk. Clinical studies included assessment of the pH effect with famotidine. In vitro dissolution was evaluated in various biorelevant media and in a pH-shift test. PK studies in dogs were conducted under pentagastrin or famotidine pre-treatment and GastroPlus was employed to model human and dog PK data and simulate the performance in human. Clinical data indicated considerable pH dependent absorption of the drug when dosed in the presence of H2-antagonists. In vitro dissolution and in vivo dog data confirmed that the observed pH effect was due to reduced dissolution rate and lower solubility at increased gastric and intestinal pH. A salt form was identified to overcome the effect by providing fast dissolution and prolonged supersaturation. GastroPlus simulations predicted a mitigation of the pH effect by the salt. The drug exhibited a strong pH-effect in humans. The in vitro, in vivo and modeling approach provides a systematic workflow to evaluate the risk of a new drug and identify a strategy able to mitigate the risk.

Biologic drugs include proteins, peptides, and nucleic acids used in prophylactic or therapeutic applications. The use of insulin for type 1 diabetes mellitus is perhaps one of the oldest uses of protein therapeutics. The modern repertoire of protein drugs also includes monoclonal antibodies (mAbs) and antibody drug conjugates (ADCs) among others. Polypeptides with more than 30 amino acids are typically defined as large molecules or biologics. In the body, an antibody is a protein produced by s-lymphocytes in response to substances recognized as foreign (“antigens”). Antibodies recognize and bind to antigens, resulting in their inactivation or opsonization or complement-mediated destruction. Biologic drug substance and drug product manufacturing processes must take into consideration the physicochemical characteristics of these molecules to ensure their stability throughout manufacture. Most therapeutic proteins are administered as aqueous solutions. Therefore, achieving and maintaining solubility is a key requirement for the manufacture, storage, and use of these biologic drugs.

The rate and extent of granule growth and densification during high-shear wet granulation (HSWG) depends on a variety of formulation and process variables, including material attributes of critical formulation excipients, such as binders. The effects of known binder attributes to the rate and extent of granule growth and densification in a wet granulation process could be either specific or agnostic to a particular active pharmaceutical ingredient (API) or drug product formulation. The effect of binder properties and process variables, such as mode of addition, on the HSWG process and product performance can be explored both experimentally as well as through in silico modeling and simulation. Examples and case studies on the effect of material attributes on process performance using both experimental and modeling methodologies are presented. This chapter demonstrates the essential role of combining multiscale models such as the mechanistic, first principles-based particle-level models, and process models with experimental observations to fully understand and characterize the role of binder attributes on the process outcomes.

Drag force flow (DFF) sensor is a process analytical technology (PAT) for real-time inline monitoring of wet mass consistency during high-shear wet granulation. The DFF probe is a hollow cylindrical pin, whose minute deflection is measured by optical strain gages. Time-dependent deflection of the pin can be connected to single granule impacts and bulk wet-mass action. When used in a granulator, sensor dynamic measurement can be characterized with force pulse magnitude (FPM), a quantity related to blade action. Time-dependent histograms of FPMs are described adequately by lognormal distribution and provide two principal outputs: mean (MFPM) and width (WFPM). These two parameters are indicative of fundamental material properties, such as shear viscosity and granule size and density, because they were changing during the granulation process. The dynamics of MFPM and WFPM could be correlated to granulation end point and used for scaleup.

Granulation transforms the shape, size, surface, and density of powders to improve their physicochemical properties and handling. Focusing primarily on pharmaceutical wet granulation, this book provides extensive and in-depth understanding of current paradigms and practices. This chapter provides broad perspectives and overviews evolving paradigms and practices in the field of pharmaceutical wet granulation including (a) processes at the interface of different technologies such as hot melt extrusion coupled with the concepts of wet granulation or dry granulation coupled with the role of water in wet granulation (e.g., moisture activated dry granulation); (b) processes that concurrently utilize heat and mass flow dynamics, such as steam granulation, melt granulation, and freeze granulation (instead of traditional methodologies that utilize only mass (liquid binder) flow); and (c) leaps of granulation technology with improvements and extensions of particular aspects, such as mode of liquid addition (e.g., foam granulation).

Co-jet-milling drugs and lubricants may enable simultaneous particle size reduction and surface coating to achieve satisfactory aerosolization performance. This study aims to establish the relationship between surface lubricant coverage and aerosolization behavior of a model drug (ciprofloxacin HCl) co-jet-milled with lubricants [magnesium stearate (MgSt) or L-leucine]. The co-jet-milled formulations were characterized for their particle size, morphology, cohesion, Carr’s index, and aerosolization performance. The surface lubricant coating was assessed by probing surface chemical composition using X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary-ion mass spectrometry (ToF-SIMS). The effects of co-jet-milling on the surface energy and in vitro dissolution of ciprofloxacin were also evaluated. Our results indicated that, in general, ciprofloxacin co-jet-milled with L-leucine at > 0.5% w/w showed a significant higher fine particle fraction (FPF) compared with the ciprofloxacin jet-milled alone. The FPF values plateau at or above 5 % w/w for both MgSt and L-leucine. We have established the quantitative correlations between surface lubricant coverage and aerosolization in the tested range for each of the lubricants. More importantly, our results suggest different mechanisms to improve aerosolization for MgSt-coating and L-leucine-coating, respectively: MgSt-coating reduces inter-particulate interactions through the formation of low surface energy coating films, while L-leucine-coating not only reduces the surface energy but also creates rough particle surfaces that reduce inter-particulate contact area. Furthermore, surface coatings with 5% w/w MgSt (which is hydrophobic) did not lead to substantial changes in in vitro dissolution. Our findings have shown that the coating structure/quality and their effects could be highly dependent on the process and the coating material. The findings from this mechanistic study provide fundamental understanding of the critical effects of MgSt and L-leucine surface coverages on aerosolization and powder flow properties of inhalation particles.

Inline focused beam reflectance measurement (FBRM) is a valuable real-time monitoring process analytical technology (PAT) for granule size distribution. Chord length distribution (CLD) reported by FBRM inline inside a high-shear granulator (HSG) can differentiate particle size distributions (PSDs) within the ranges relevant to pharmaceutical processing. The CLD changes during processing is indicative of the progression of granulation, reproducibly delineates the effects of water amount, binder concentration, and impeller tip speed on the progress and outcome of wet granulation and correlates well with offline PSD measured by nested sieve analyses. The FBRM data can be tracked using an end-point indication algorithm, which assesses the process time needed to reach the target CLD and be useful for process monitoring and scaleup. This chapter highlights key studies that establish the capability of FBRM as a HSWG PAT exemplifying case studies of granulations whose end point is determined predominantly by granule growth (a placebo) or reduction of fines (an active formulation).

This chapter describes the use of a drag force flow (DFF) sensor to probe wet mass consistency in real time and its correlation to granule densification using two formulations. A placebo and a brivanib alaninate formulation were granulated with different concentrations of binder or water, respectively, while comparing DFF sensor response with granule size growth and densification assessed independently. The wet mass consistency parameter correlated well with granule densification, which is known as a critical material attribute that correlated with tablet dissolution. In addition, comparison of responses from focused beam reflectance measurement (FBRM) and DFF sensors are presented to assess complementarity of information on granulation progress from the two probes. The DFF sensor was able to quantitatively characterize with high resolution a response of wet mass consistency distinct from granule size distribution. Finally, application of DFF sensor to scaleup of granulation is demonstrated.

The force exerted by wet mass in a granulator on a thin cylindrical probe called the drag force flow (DFF) sensor reflects wet mass consistency and is indicative of the granule densification. Comparison of flow force during wet granulation of batches with different binder concentration indicated good correlation with the granulation's resistance to flow and interparticulate interactions measured by the FT4 Powder Rheometer. This indicated that the force pulse magnitude (FPM) measured by the DFF sensor was indicative of fundamental material properties (e.g., shear viscosity and granule size/density). In addition, the time-profile of the FPM signal from the DFF sensor compared well with that of the impeller amperage, with consistent differentiation between different formulations.

This chapter provides an integrated case study on the systematic application of quality-by-design (QbD) to product development and demonstrates the implementation of QbD concepts in the different aspects of product and process design for a drug product manufactured by a wet granulation process. Using a risk-based approach, the strategy for development entailed identification of product critical quality attributes (CQAs), assessment of risks to the CQAs and performing experiments to understand and mitigate identified risks. Quality risk assessments and design of experiments (DOEs) were performed to understand the quality of the input raw materials required for a robust formulation and the impact of manufacturing process parameters on CQAs. In addition to material property and process parameter controls, the control strategy includes use of process analytical technology (PAT), as well as conventional analytical tests, to control in-process material attributes and ensures quality of the final product.

Formation of isoaspartate (IsoAsp) from spontaneous asparagine (Asn) deamidation or aspartate (Asp) isomerization is one of the most common non-enzymatic pathways of chemical degradation of protein and peptide pharmaceuticals. Rapid quantitation of IsoAsp formation can enable rank-ordering of potential drug candidates, mutants, and formulations as well as support shelf life prediction and stability requirements. A coupled enzymatic fluorescence-based IsoAsp assay (CEFIA) was developed as a high-throughput method for quantitation of IsoAsp in peptides and proteins. In this note, application of this method to two therapeutic candidate proteins with distinct structural scaffolds is described. In addition, the results obtained with this method are compared to those from conventional assays.

Pulmonary drug delivery is a non-invasive and effective route for local or systemic drug administration. Despite several products in the market, the mechanism of drug absorption from the lungs is not well understood. An in vitro model for aerosol deposition and transport across epithelia that uses particle deposition may be a good predictor of and help understand in vivo drug disposition. The objective of this study was to examine the uptake of HFA fluticasone (Flovent HFA) particles at various stages of the Next Generation Impactor (NGI) by human Calu-3 cell line derived from human bronchial respiratory epithelial cell monolayer. Particles were directly deposited on Calu-3 cells incorporated onto stages 3, 5, and 7 of the NGI at the air-liquid interface (ALI). We modified the NGI apparatus to allow particle deposition directly on cells and determined the in vitro deposition characteristics using modified NGI. Particles of different size ranges showed different in vitro epithelial transport rates. This study highlights the need to develop in vitro test systems to determine the deposition of aerosol particles on cell monolayers by simultaneously considering aerodynamic properties.

There is an overgrowing emphasis on supersaturating drug delivery systems (SDDS) with increase in number of poorly water-soluble compounds. However, biopharmaceutical performance from these formulations is limited by phase transformation to stable crystalline form due to their high-energy physical form. In the present study, in vitro kinetic solubility in water and dissolution in biorelevant medium integrated with in silico physiologically based pharmacokinetic (PBPK) modeling was used to predict biopharmaceutical performance of SDDS of poorly water-soluble compound, carbamazepine (CBZ). GastroPlus™ with advanced compartmental absorption and transit model was used as a simulation tool for the study. Wherein, the model was developed using physicochemical properties of CBZ and disposition parameters obtained after intravenous administration of CBZ (20 mg/kg) into Sprague-Dawley (SD) rats. Biorelevant medium was selected by screening different dissolution media for their capability to predict oral plasma concentration-time profile of marketed formulation of CBZ. In vivo performance of SDDS was predicted with the developed model and compared to observed plasma concentration-time profile obtained after oral administration of SDDS into SD rats (20 mg/kg). The predictions, with strategy of using kinetic solubility and dissolution in the selected biorelevant medium, were consistent with observed biopharmaceutical performance of SDDS. Additionally, phase transformation of CBZ during gastrointestinal transit of formulations was evaluated and correlated with in vivo dissolution deconvoluted by Loo-Reigelman analysis.

Physical tablet defects are related to internal structural defects that are not easily assessed by the traditional methods, such as dusting, laminating, or fracturing during appearance, friability, or hardness testing. Also, these methods do not allow objective and quantitative investigation of the role of formulation and process variables, which is essential for quality-by-design drug product development. In this study, an X-ray microcomputed tomography (XμCT) method to analyze internal tablet defects is developed using tablets from a quality-by-design design-of-experiment study. The design of experiment investigated the effect of roller compaction roll force, filler composition, and the amount of magnesium stearate on tablet quality attributes. Average contiguous void volume by optical image processing and fracture size distribution and direction by artificial intelligence-based image processing quantified the internal tablet fracture severity. XμCT increased formulation and process knowledge in support of scale-up manufacturing. We demonstrated how XμCT can be incorporated as a part of a holistic approach to quantitatively identify and mechanistically assess the risks of internal tablet defects. Furthermore, expanding the use of XμCT with an artificial intelligence-based quantitative analysis can deepen our tableting knowledge from an empirical understanding to a mechanistic understanding of compaction phenomenon.

Real-time monitoring and control of high shear wet granulation (HSWG) using process analytical technologies is crucial to process design, scale-up, and reproducible manufacture. Although significant progress has been made in real-time measurement of granule size distribution using focused beam reflectance measurement (FBRM), real-time in-line assessment of granule densification remains challenging. In this study, a drag force flow (DFF) sensor was developed and used to probe wet mass consistency in real-time. In addition, responses from FBRM and DFF sensors were compared to assess complementarity of information on granulation progress from the two probes. A placebo and a brivanib alaninate formulation were granulated with different concentrations of binder or water, respectively, while measuring granule size growth, densification, and DFF sensor response. The DFF sensor was able to quantitatively characterize with high resolution a response of wet mass consistency distinct from granule size distribution. The wet mass consistency parameter correlated well with granule densification, which was shown as a critical material attribute that correlated with tablet dissolution. In addition, application of DFF sensor to scale-up of granulation was demonstrated. These results showed the value of wet mass consistency measurement using DFF for WG monitoring and control.

Compromised oral drug absorption, due to poor aqueous solubility, is one of the major challenges faced by the pharmaceutical industry in the drug discovery and development process. Scientific community is striving to develop tools for accurate prediction of the oral absorption profile of drugs. Weak bases form a major class of drugs exhibiting poor aqueous solubility. Numerous tools such as biorelevant in vitro dissolution testing and in silico modeling are being developed to investigate and understand the in vivo absorption and pharmacokinetics for this class of drugs. Biorelevant dissolution coupled with physiologically based pharmacokinetics (PBPK) modeling has fast emerged as a reliable tool to support pharmaceutical development and minimize the need for animal/human testing. The present review discusses the evolution, present status, and future trends on the applicability of these techniques for predicting oral absorption and pharmacokinetics of poorly soluble weakly basic drugs.

Excipient selection is based on their functionality, compatibility, and variability of critical material attributes within an acceptable range for a given drug product. Drug-excipient compatibility studies are usually used as a screening tool to identify potential incompatibilities that alter physical, chemical, microbiological, or therapeutic properties of the drug in the dosage form. Excipient functionality involves the identification of critical material attributes based on target material properties and the functionality-related characteristics that impact the in-process and finished product quality attributes. Understanding the mechanistic basis of functional role and the commonly encountered range of variability of excipient attributes helps identify the acceptable range of excipient variability in a given drug product. This chapter describes contemporary practices in the identification of functionality-related characteristics of excipients; compatibility study designs and data interpretation; and understanding excipient variability and its impact on drug product quality attributes with examples and case studies.

This study reports an experimental approach to determine the contribution from two different components of surface energy on cohesion. A method to tailor the surface chemistry of mefenamic acid via silanization is established and the role of surface energy on cohesion is investigated. Silanization was used as a method to functionalize mefenamic acid surfaces with four different functional end groups resulting in an ascending order of the dispersive component of surface energy. Furthermore, four haloalkane functional end groups were grafted on to the surface of mefenamic acid, resulting in varying levels of acid-base component of surface energy, while maintaining constant dispersive component of surface energy. A proportional increase in cohesion was observed with increases in both dispersive as well as acid-base components of surface energy. Contributions from dispersive and acid-base surface energy on cohesion were determined using an iterative approach. Due to the contribution from acid-base surface energy, cohesion was found to increase ∼11.7× compared to the contribution from dispersive surface energy. Here, we provide an approach to deconvolute the contribution from two different components of surface energy on cohesion, which has the potential of predicting powder flow behavior and ultimately controlling powder cohesion.

A quality by design approach was applied to the development of brivanib alaninate tablets. Brivanib alaninate, an ester pro-drug, undergoes hydrolysis to its parent compound, BMS-540215. The shelf-life of the tablets is determined by the rate of the hydrolysis reaction. Hydrolysis kinetics in the tablets was studied to understand its dependence on temperature and humidity. The BMS-540215 amount versus time profile was simulated using a kinetic model for the formation of BMS-540215 as function of relative humidity in the environment and a sorption-desorptiom moisture transfer model for the relative humidity inside the package. The combined model was used to study the effect of initial tablet water content on the rate of degradation and to identify a limit for initial tablet water content that results in acceptable level of the degradant at the end of shelf-life. A strategy was established for the moisture and degradant control in the tablet based on the understanding of its stability behavior and mathematical models. The control strategy includes a specification limit on the tablet water content and manufacturing process controls that achieve this limit at the time of tablet release testing.

The molecular basis of crystal surface adhesion leading to sticking was investigated by exploring the correlation of crystal adhesion to oxidized iron coated atomic force microscope (AFM) tips and bulk powder sticking behavior during tableting of two morphologically different crystals of a model drug, mefenamic acid (MA), to differences in their surface functional group orientation and energy. MA was recrystallized into two morphologies (plates and needles) of the same crystalline form. Crystal adhesion to oxidized iron coated AFM tips and bulk powder sticking to tablet punches was assessed using a direct compression formulation. Surface functional group orientation and energies on crystal faces were modeled using Accelrys Material Studio software. Needle-shaped morphology showed higher sticking tendency than plates despite similar particle size. This correlated with higher crystal surface adhesion of needle-shaped morphology to oxidized iron coated AFM probe tips, and greater surface energy and exposure of polar functional groups. Higher surface exposure of polar functional groups correlates with higher tendency to stick to metal surfaces and AFM tips, indicating involvement of specific polar interactions in the adhesion behavior. In addition, an AFM method is identified to prospectively assess the risk of sticking during the early stages of drug development.