Impact of Critical Material Attributes (CMAs)-Particle Shape on Miniature Pharmaceutical Unit Operations.

The U.S. Food and Drug Administration (FDA) emphasizes drug product development by Quality by Design (QbD). Critical material attributes (CMAs) are a QbD element that has an impact on pharmaceutical operations and product quality. Pharmaceutical drugs often crystallize as needle-shaped (a CMA) particles and affect the process due to poor flowability, low bulk density, and high compressibility, and eventually the product performance. In this study, the product obtained from crystallization was needle-shaped Ciprofloxacin HCl (CIPRO), formed lumps during drying, and compacted during processing through feeders. To delump small amounts of materials and break the needles, multiple available devices (mortar-pestle, Krups grinder) and custom-made grinder were assessed before formulation. The processed CIPRO powder was then used to make tablets in the miniature tablet manufacturing unit developed by the team at MIT. The critical quality attributes (CQA) of the tablets, set by the United States Pharmacopeia (USP), were then assessed for the drug powder processed with each of these devices. Powder properties comparable to commercial CIPRO were obtained when the custom MIT-designed grinder was used, leading to tablets that meet the USP criteria, with comparable dissolution profiles of those for marketed CIPRO tablets. This study demonstrates how needle-shaped crystals have an impact on pharmaceutical operations, even if it is on a miniature scale, and how proper shape and subsequent flow properties can be obtained by processing the particles through the MIT team-designed grinder.

On-Demand Manufacturing of Direct Compressible Tablets: Can Formulation Be Simplified?

PURPOSE: Oral direct compressible tablets are the most frequently used drug products. Manufacturing of tablets requires design and development of formulations, which need a number of excipients. The choice of excipients depends on the concentration, manufacturability, stability, and bioavailability of the active pharmaceutical ingredients (APIs). At MIT, we developed a miniature platform for on-demand manufacturing of direct compressible tablets. This study investigated how formulations could be simplified to use a small number of excipients for a number of different API's in which long term stability is not required. METHOD: Direct compressible tablets of five pharmaceutical drugs, Diazepam, Diphenhydramine HCl, Doxycycline Monohydrate, Ibuprofen, and Ciprofloxacin HCl, with different drug loadings, were made using direct compression in an automated small scale system.. The critical quality attributes (CQA) of the tablets were assessed for the quality standards set by the United States Pharmacopeia (USP). RESULTS: This miniature system can manufacture tablets - on-demand from crystalline API using the minimum number of excipients required for drug product performance. All drug tablets met USP quality standards after manufacturing and after 2 weeks of accelerated stability test, except for slightly lower drug release for Ibuprofen. CONCLUSIONS: On-demand tablets manufacturing where there is no need for long term stability using a flexible, miniature, automated (integrated) system will simplify pharmaceutical formulation design compared to traditional formulations. This advancement will offer substantial economic benefits by decreasing product time-to-market and enhancing quality.

Advanced Continuous Flow Platform for On-Demand Pharmaceutical Manufacturing.

As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufacturing including the large production footprint and lengthy time-scale, we previously reported a refrigerator-sized continuous flow system for the on-demand production of essential medicines. Building on this technology, herein we report a second-generation, reconfigurable and 25 % smaller (by volume) continuous flow pharmaceutical manufacturing platform featuring advances in reaction and purification equipment. Consisting of two compact [0.7 (L)×0.5 (D)×1.3 m (H)] stand-alone units for synthesis and purification/formulation processes, the capabilities of this automated system are demonstrated with the synthesis of nicardipine hydrochloride and the production of concentrated liquid doses of ciprofloxacin hydrochloride, neostigmine methylsulfate and rufinamide that meet US Pharmacopeia standards.

General Method for the Identification of Crystal Faces Using Raman Spectroscopy Combined with Machine Learning and Application to the Epitaxial Growth of Acetaminophen.

Crystal morphology is one of the key crystallographic characteristics that governs the macroscopic properties of crystalline materials. The identification of crystal faces, or face indexing, is an important technique that is used to get information regarding a crystal's morphology. However, it is mainly limited to single crystal X-ray diffraction (SCXRD) and it is often not applicable to products of routine crystallizations becasue it requires high quality single crystals in a narrow size range. To overcome the limitations of the SCXRD method, we have developed a robust and convenient Raman face indexing method based on work by Moriyama et al. This method exploits small but detectable differences in Raman spectra of crystal faces caused by different orientations of the crystallographic axis relative to the direction and polarization of the excitation laser beam. The method requires the compilation of a Raman spectral library for each compound and must be built and validated by SCXRD face indexing. Once the spectral library is available for a compound, the identity of unknown crystal faces (from any crystal that is larger than laser beam) can be inferred by collecting and comparing the Raman spectra to spectra within the library. We have optimized this approach further by developing a machine-learning algorithm that identifies crystal faces by performing a statistical comparison of the spectra in the Raman library and the Raman spectra of the unknown crystal faces. Here, we report the development of the Raman face indexing method and apply it to three different epitaxial systems: Acetaminophen (APAP) grown as an overlayer crystal on d-mannitol (MAN), d-galactose (GAL), and xylitol (XYL) substrates. For each of these epitaxial systems, the crystals were grown under various experimental conditions and have a wide range of sizes and quality. Using the Raman face indexing method, we were able to perform high-throughput indexing of a large number of crystals from different crystallization conditions, which could not be achieved using SCXRD or other analytical techniques.

The A Priori Design and Selection of Ionic Liquids as Solvents for Active Pharmaceutical Ingredients.

In this paper we derive a straightforward computational approach to predict the optimal ionic liquid (IL) solvent for a given compound, based on COSMO-RS calculations. These calculations were performed on 18 different active pharmaceutical ingredients (APIs) using a matrix of 210 hypothetical ILs. These results indicated that the 18 APIs could be classified into three distinct categories based on their relative hydrogen bond donating or accepting ability, with similar optimal IL solvent predictions within each class. Informed by these results, a family of strongly hydrogen bond donating ILs based on the N-alkylguanidinium cation were prepared and characterized. The solubility of the APIs in each of these classes was found to be qualitatively consistent with the predictions of the COSMO-RS model. The suitability of these novel guanidinium salts as crystallization solvents was demonstrated by the use of N-butylguanidinium bis(trifluoromethanesulfonyl)imide for the purification of crude fenofibrate using dimethylsulfoxide as an antisolvent, which resulted in good yields and excellent purities. Finally, a simple descriptor based model is proposed to suggest the best IL solvent for arbitrary APIs.

Separate mechanisms of ion oligomerization tune the physicochemical properties of n-butylammonium acetate: cation-base clusters vs. anion-acid dimers.

We investigated the ability of the ions comprising protic ionic liquids to strongly interact with their neutral acid and base forms through the characterization of n-butylammonium acetate ([C4NH3][OAc]) in the presence of excess n-butylamine (C4NH2) or excess acetic acid (HOAc). The conjugate and parent acid or base form new nonstoichiometric, noncovalently bound species (i.e., oligomeric ions) which change the physical and chemical properties of the resulting liquids, thus offering tunability. The effects of adding C4NH2 or HOAc to [C4NH3][OAc] on the resulting thermal and spectroscopic properties differ and suggest that C4NH2 interacts primarily with [C4NH3]+ to form 3-dimensional polymeric networks likely similar to those in H2O/[H3O]+, while HOAc interacts primarily with [OAc]- to form oligomeric ions (e.g., [H(OAc)2]-). The densities of the systems increased with the increase of acid content and reached a maximum when the acid molar fraction was 0.90, but decreased with increasing amine concentration. The viscosities decreased significantly with increasing acid or base concentration. The solvent properties of the mixtures were assessed by measuring the solubilities of benzene, ethyl acetate, diethyl ether, heptane, ibuprofen free acid, and lidocaine free base. The solubilities of the organic solutes and active pharmaceutical ingredients can be tuned with the concentration of acid or amine in the mixtures. In addition, crystallization of the active pharmaceutical ingredients can be induced with the modification of the composition of the mixtures. These observations support the usage of these mixtures for the synthesis and purification of acid or basic active pharmaceutical ingredients in the pharmaceutical industry.

Ionic fluids containing both strongly and weakly interacting ions of the same charge have unique ionic and chemical environments as a function of ion concentration.

Liquid multi-ion systems made by combining two or more salts can exhibit charge ordering and interactions not found in the parent salts, leading to new sets of properties. This is investigated herein by examining a liquid comprised of a single cation, 1-ethyl-3-methylimidazolium ([C2mim](+)), and two anions with different properties, acetate ([OAc](-)) and bis(trifluoromethylsulfonyl)imide ([NTf2](-)). NMR and IR spectroscopy indicate that the electrostatic interactions are quite different from those in either [C2mim][OAc] or [C2mim][NTf2]. This is attributed to the ability of [OAc](-) to form complexes with the [C2mim](+) ions at greater than 1:1 stoichiometries by drawing [C2mim](+) ions away from the less basic [NTf2](-) ions. Solubility studies with molecular solvents (ethyl acetate, water) and pharmaceuticals (ibuprofen, diphenhydramine) show nonlinear trends as a function of ion content, which suggests that solubility can be tuned through changes in the ionic compositions.

Understanding and Analyzing Freezing-Point Transitions of Confined Fluids within Nanopores.

Understanding phase transitions of fluids confined within nanopores is important for a wide variety of technological applications. It is well known that fluids confined in nanopores typically demonstrate freezing-point depressions, ΔTf, described by the Gibbs-Thomson (GT) equation. Herein, we highlight and correct several thermodynamic inconsistencies in the conventional use of the GT equation, including the fact that the enthalpy of melting, ΔHm, and the solid-liquid surface energy, γ(SL), are functions of pore diameter, complicating their prediction. We propose a theoretical analysis that employs the Turnbull coefficient, originally derived from metal nucleation theory, and show its consistency as a more reliable quantity for the prediction of ΔTf. This analysis provides a straightforward method to estimate ΔTf of nanoconfined organic fluids. As an example, we apply this technique to ibuprofen, an active pharmaceutical ingredient (API), and show that this theory fits well to the experimental ΔTf of nanoconfined ibuprofen.

Concluding remarks.

Crystallization from solution is a crucial process used in the manufacture of a wide variety of materials. The first step in the crystallization process is the birth of a new crystalline phase, which is known as nucleation. Nucleation plays a key role in determining the results of any crystallization process with respect to the size, shape and crystal form obtained. Classical nucleation theory does not adequately explain the crystal nucleation process. Work described in the literature and at this Faraday Discussion describe more complex nucleation mechanisms which are generally known as two-step nucleation models. In addition, as most nucleation is influenced by dust, dirt and container surfaces, the importance of heterogeneous nucleation and the use of templates to accelerate nucleation and influence crystal form are promising methods for the study and control of nucleation. It is also clear from this Faraday Discussion that interest in this topic has grown, and new and novel experimental and modeling approaches are being used for the study of crystal nucleation from solution.

Formation of Organic Molecular Nanocrystals under Soft Confinement.

Methods to produce nano-sized organic molecular crystals in thin films are of great interest in the pharmaceutical industry due to the potential benefit of increased solubility of poorly soluble drugs and the advantages of film-based dosage forms over traditional tablet/capsule-based dosage form. One method to directly form organic nanocrystals is by crystallization in confined environments where the overall crystallization volume is constrained. We report the use of a novel solution impregnation method to form nanocrystals in polymer matrices with various microstructures in order to study the structure of the confined nanocrystals and the role of soft confinement and polymer chemistry on the nucleation process of nano-sized crystals. The particle diameter correlates with the microstructure of the polymer matrices and the nucleation kinetics. In addition, by carefully choosing the experimental conditions and the polymer matrix, polymorph control of nanocrystals can be achieved. Solid-state nuclear magnetic resonance (ssNMR) was used to examine the local structure of nanocrystals inside the polymer matrices and crystal polymer interactions. This method may serve as a novel formulation method to obtain nanocrystals of poorly soluble active pharmaceutical ingredients (APIs) for pharmaceutical industry.

On the connection between nonmonotonic taste behavior and molecular conformation in solution: The case of rebaudioside-A.

The diterpene steviol glycoside, rebaudioside A, is a natural high potency non-caloric sweetener extracted from the leaves of Stevia rebaudiana. This compound shows a parabolic change in sweet taste intensity with temperature which contrasts with the general finding for other synthetic or natural sweeteners whose sweet taste increases with temperature. The nonmonotonic taste behavior was determined by sensory analysis using large taste panels. The conformational landscape of rebaudioside A was established at a range of temperatures by means of nuclear magnetic resonance and molecular dynamics simulation. The relationship between various conformations and the observed sweetness of rebaudioside A is described.

Self-association during heterogeneous nucleation onto well-defined templates.

We investigated the interplay between self-associates in solution and surface templating by studying the crystallization behavior of isonicotinamide (INA) and 2,6-dihydroxybenzoic acid (DHB) in the presence of self-assembled monolayers (SAM). The end group of the SAM as well as the hydrogen-bonding capabilities of the solvent and self-association of INA and DHB were found to be important in polymorph crystallization on SAMs. In the case of INA in ethanol, both chain and dimer self-associates are present in the solution. In the absence of SAMs the polymorph form II (dimer structure) is the crystallization outcome. In ethanol the 4-mercaptopyridine and 4-mercaptobenzoic acid SAMs organize INA chain associates at the template surface and enable the crystallization of form I while the 16-mercaptohexadecanoic acid SAM results in the crystallization of form II. Raman spectroscopy suggests that molecular interactions between INA and the SAM are responsible for the formation of specific polymorphs. XRPD results in the identification of the orientation of the crystal on the surface that further verified the results obtained by Raman spectroscopy. In nitrobenzene and nitromethane INA associates in solution only as chains and crystallization results in the formation of form IV and form I, respectively (both chain forms). The crystals formed in the bulk solution and on SAMs were the same, which seems to indicate that the self-association in nitrobenzene and nitromethane is not influenced by the presence of templates. In the case of DHB in toluene and chloroform, all three SAMs nucleated only one type of polymorph (stable form 2). In the case of toluene the polymorphic outcome was stable form 2 instead of metastable form 1, which is favored in toluene in the absence of the SAMs. Again, Raman spectroscopy and XRPD suggest that DHB-SAM molecular interactions may be responsible for the formation of form 2.

Raman spectroscopy and one-dimensional convolutional neural network modeling as a real-time monitoring tool for in vitro transaminase-catalyzed synthesis of a pharmaceutically relevant amine precursor.

Raman spectroscopy has been used to measure the concentration of a pharmaceutically relevant model amine intermediate for positive allosteric modulators of nicotinic acetylcholine receptor in a ω-transaminase-catalyzed conversion. A model based on a one-dimensional convolutional neural network was developed to translate raw data augmented Raman spectra directly into substrate concentrations, with which the conversion from ketone to amine by ω-transaminase could be determined over time. The model showed very good predictive capabilities, with R2 values higher than 0.99 for the spectra included in the modeling and 0.964 for an independent dataset. However, the model could not extrapolate outside the concentrations specified by the model. The presented work shows the potential of Raman spectroscopy as a real-time monitoring tool for biocatalytic reactions.

Templated nucleation of acetaminophen on spherical excipient agglomerates.

We investigated the effect of spherical agglomeration of heterogeneous crystalline substrates on the nucleation of acetaminophen (AAP). Optical and electron microscopy showed that the surface morphologies of single crystal triclinic lactose and D-mannitol differed significantly from their counterparts formed via spherical agglomeration. Spherical agglomerates of lactose were shown to enhance the nucleation rate of acetaminophen (AAP) by a factor of 11 compared to single crystal lactose; however, no such enhancement was observed for D-mannitol. X-ray powder diffraction identified the presence of new crystal faces of lactose present only in the spherical agglomerates However, D-mannitol did not show any significant change in crystal morphology. The new crystal faces of triclinic lactose were analyzed using geometric lattice matching software and molecular dynamics simulations to establish any new and significant epitaxial matches between lactose and AAP. A coincident lattice match and a large favorable energy interaction from hydrogen bonding were observed between the (141¯) and (001) crystal faces of lactose and AAP, respectively. The enhanced nucleation kinetics, X-ray data, and computational studies indicated that the spherical crystallization of lactose exposed the (141¯) face on the surface of the agglomerates, which subsequently enhanced the nucleation rate of AAP through geometric lattice matching and molecular functionality. This study highlights the importance of exploring different heterogeneous substrate morphologies for enhancing nucleation kinetics.

Electrospun formulations containing crystalline active pharmaceutical ingredients.

PURPOSE: To investigate the use of electrospinning for forming solid dispersions containing crystalline active pharmaceutical ingredients (API) and understand the relevant properties of the resulting materials. METHOD: Free surface electrospinning was used to prepare nanofiber mats of poly(vinyl pyrrolidone) (PVP) and crystalline albendazole (ABZ) or famotidine (FAM) from a suspension of the drug crystals in a polymer solution. SEM and DSC were used to characterize the dispersion, XRD was used to determine the crystalline polymorph, and dissolution studies were performed to determine the influence of the preparation method on the dissolution rate. RESULTS: The electrospun fibers contained 31 wt% ABZ and 26 wt% FAM for the 1:2 ABZ:PVP and 1:2 FAM:PVP formulations, respectively, and both APIs retained their crystalline polymorphs throughout processing. The crystals had an average size of about 10 µm and were well-dispersed throughout the fibers, resulting in a higher dissolution rate for electrospun tablets than for powder tablets. CONCLUSIONS: Previously used to produce amorphous formulations, electrospinning has now been demonstrated to be a viable option for producing fibers containing crystalline API. Due to the dispersion of the crystals in the polymer, tablets made from the fiber mats may also exhibit improved dissolution properties over traditional powder compression.

End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation.

A series of tubes: The continuous manufacture of a finished drug product starting from chemical intermediates is reported. The continuous pilot-scale plant used a novel route that incorporated many advantages of continuous-flow processes to produce active pharmaceutical ingredients and the drug product in one integrated system.

Extracting particle size distribution from laser speckle with a physics-enhanced autocorrelation-based estimator (PEACE).

Extracting quantitative information about highly scattering surfaces from an imaging system is challenging because the phase of the scattered light undergoes multiple folds upon propagation, resulting in complex speckle patterns. One specific application is the drying of wet powders in the pharmaceutical industry, where quantifying the particle size distribution (PSD) is of particular interest. A non-invasive and real-time monitoring probe in the drying process is required, but there is no suitable candidate for this purpose. In this report, we develop a theoretical relationship from the PSD to the speckle image and describe a physics-enhanced autocorrelation-based estimator (PEACE) machine learning algorithm for speckle analysis to measure the PSD of a powder surface. This method solves both the forward and inverse problems together and enjoys increased interpretability, since the machine learning approximator is regularized by the physical law.

Gel-induced selective crystallization of polymorphs.

Although nanoporous materials have been explored for controlling crystallization of polymorphs in recent years, polymorphism in confined environments is still poorly understood, particularly from a kinetic perspective, and the role of the local structure of the substrate has largely been neglected. Herein, we report the use of a novel material, polymer microgels with tunable microstructure, for controlling polymorph crystallization from solution and for investigating systematically the effects of nanoconfinement and interfacial interactions on polymorphic outcomes. We show that the polymer microgels can improve polymorph selectivity significantly. The polymorphic outcomes correlate strongly with the gel-induced nucleation kinetics and are very sensitive to both the polymer microstructure and the chemical composition. Further mechanistic investigations suggest that the nucleation-templating effect and the spatial confinement imposed by the polymer network may be central to achieving polymorph selectivity. We demonstrate polymer microgels as promising materials for controlling crystal polymorphism. Moreover, our results help advance the fundamental understanding of polymorph crystallization at complex interfaces, particularly in confined environments.

The role of nanopore shape in surface-induced crystallization.

Crystallization of a molecular liquid from solution often initiates at solid-liquid interfaces, and nucleation rates are generally believed to be enhanced by surface roughness. Here we show that, on a rough surface, the shape of surface nanopores can also alter nucleation kinetics. Using lithographic methods, we patterned polymer films with nanopores of various shapes and found that spherical nanopores 15-120 nm in diameter hindered nucleation of aspirin crystals, whereas angular nanopores of the same size promoted it. We also show that favourable surface-solute interactions are required for angular nanopores to promote nucleation, and propose that pore shape affects nucleation kinetics through the alteration of the orientational order of the crystallizing molecule near the angles of the pores. Our findings have clear technological implications, for instance in the control of pharmaceutical polymorphism and in the design of 'seed' particles for the regulation of crystallization of fine chemicals.

Free surface electrospinning of fibers containing microparticles.

Many materials have been fabricated using electrospinning, including pharmaceutical formulations, superhydrophobic surfaces, catalysis supports, filters, and tissue engineering scaffolds. Often these materials can benefit from microparticles included within the electrospun fibers. In this work, we evaluate a high-throughput free surface electrospinning technique to prepare fibers containing microparticles. We investigate the spinnability of polyvinylpyrrolidone (PVP) solutions containing suspended polystyrene (PS) beads of 1, 3, 5, and 10 µm diameter in order to better understand free surface electrospinning of particle suspensions. PS bead suspensions with both 55 kDa PVP and 1.3 MDa PVP were spinnable at 1:10, 1:5, and 1:2 PS:PVP mass loadings for all particle sizes studied. The final average fiber diameters ranged from 0.47 to 1.2 µm and were independent of the particle size and particle loading, indicating that the fiber diameter can be smaller than the particles entrained and can furthermore be adjusted based on solution properties and electrospinning parameters, as is the case for electrospinning of solutions without particles.