Analytical quality by design approach for the determination of imidazole in sildenafil API and its formulations using zwitterionic HILIC stationary phase.

Herein, the development of a HILIC method for the determination of imidazole (Imp E) in sildenafil citrate API and its final formulations is reported. The main goal of this study was to develop a robust, application-specific HPLC method according to the Analytical Quality by Design principles for the analysis of the above impurity. After the risk assessment study, the high-risk method parameters were sequentially screened and optimized by using 2-level fractional factorial and Box-Behnken designs. The mathematical models were combined with the Monte-Carlo simulations to identify the Method Operable Design Region. The method was thoroughly validated between 25 % and 150 % of the target concentration limit of the imidazole using the total-error concept. The relative bias varied between 1.6 % and 5.6 % and the RSD values were lower than 5.8 % for repeatability and intermediate precision. The limit of detection and the lower limit of quantification were satisfactory and found to be 0.025 and 0.125 µg mL-1 imidazole, respectively. The applicability of the proposed approach has been demonstrated in the analysis of several sildenafil citrate API batches and final products.

Integrating Elastic Tensor and PC-SAFT Modeling with Systems-Based Pharma 4.0 Simulation, to Predict Process Operations and Product Specifications of Ternary Nanocrystalline Suspensions.

Comminution of BCS II APIs below the 1 µm threshold followed by solidification of the obtained nanosuspensions improves their dissolution properties. The breakage process reveals new crystal faces, thus creating altered crystal habits of improved wettability, facilitated by the adsorption of stabilizing polymers. However, process-induced transformations remain unpredictable, mirroring the current limitations of our atomistic level of understanding. Moreover, conventional equations of estimating dissolution, such as Noyes-Whitney and Nernst-Brunner, are not suitable to quantify the solubility enhancement due to the nanoparticle formation; hence, neither the complex stabilizer contribution nor the adsorption influence on the interfacial tension occurring between the water and APIs is accounted for. For such ternary mixtures, no numeric method exists to correlate the mechanical properties with the interfacial energy, capable of informing the key process parameters and the thermodynamic stability assessment of nanosuspensions. In this work, an elastic tensor analysis was performed to quantify the API stability during process implementation. Moreover, a novel thermodynamic model, described by the stabilizer-coated nanoparticle Gibbs energy anisotropic minimization, was structured to predict the material's system solubility quantified by the application of PC-SAFT modeling. Comprehensively merging elastic tensor and PC-SAFT analysis into the systems-based Pharma 4.0 algorithm provided a validated, multi-level, built-in method capable of predicting the critical material quality attributes and corresponding key process parameters.

Pharma 4.0 Continuous mRNA Drug Products Manufacturing.

Continuous mRNA drugs manufacturing is perceived to nurture flow processes featuring quality by design, controlled automation, real time validation, robustness, and reproducibility, pertaining to regulatory harmonization. However, the actual adaptation of the latter remains elusive, hence batch-to-continuous transition would a priori necessitate holistic process understanding. In addition, the cost related to experimental, pilot manufacturing lines development and operations thereof renders such venture prohibitive. Systems-based Pharmaceutics 4.0 digital design enabling tools, i.e., converging mass and energy balance simulations, Monte-Carlo machine learning iterations, and spatial arrangement analysis were recruited herein to overcome the aforementioned barriers. The primary objective of this work is to hierarchically design the related bioprocesses, embedded in scalable devices, compatible with continuous operation. Our secondary objective is to harvest the obtained technological data and conduct resource commitment analysis. We herein demonstrate for first time the feasibility of the continuous, end-to-end production of sterile mRNA formulated into lipid nanocarriers, defining the equipment specifications and the desired operational space. Moreover, we find that the cell lysis modules and the linearization enzymes ascend as the principal resource-intensive model factors, accounting for 40% and 42% of the equipment and raw material, respectively. We calculate MSPD 1.30-1.45 €, demonstrating low margin lifecycle fluctuation.

Polyelectrolyte Matrices in the Modulation of Intermolecular Electrostatic Interactions for Amorphous Solid Dispersions: A Comprehensive Review.

Polyelectrolyte polymers have been widely used in the pharmaceutical field as excipients to facilitate various drug delivery systems. Polyelectrolytes have been used to modulate the electrostatic environment and enhance favorable interactions between the drug and the polymer in amorphous solid dispersions (ASDs) prepared mainly by hot-melt extrusion. Polyelectrolytes have been used alone, or in combination with nonionic polymers as interpolyelectrolyte complexes, or after the addition of small molecular additives. They were found to enhance physical stability by favoring stabilizing intermolecular interactions, as well as to exert an antiplasticizing effect. Moreover, they not only enhance drug dissolution, but they have also been used for maintaining supersaturation, especially in the case of weakly basic drugs that tend to precipitate in the intestine. Additional uses include controlled and/or targeted drug release with enhanced physical stability and ease of preparation via novel continuous processes. Polyelectrolyte matrices, used along with scalable manufacturing methods in accordance with green chemistry principles, emerge as an attractive viable alternative for the preparation of ASDs with improved physical stability and biopharmaceutic performance.

Development of agomelatine nanocomposite formulations by wet media milling.

Nanocrystal formulations of the BCS class II agomelatine, were developed by wet media milling. The most suitable stabilizer was identified and effects of process and formulation variables on the nanocrystal size and ζ-potential were evaluated employing a Box-Behnken experimental design. The optimized nanosuspensions were dried and subsequently evaluated for redispersibility and physicochemical properties. Computational simulation of solid state properties was applied to rationalize crystal fracture. It was found that low viscosity hydroxypropylcellulose with sodium dodecyl sulfate is the most suitable stabilizer. Stabilizer concentration exerts a statistically significant effect on particle size, which depends on the mill's rotation speed. The milling process induces a polymorphic transition to form II, which could affect size reduction kinetics. The solidified nanosuspensions' redispersibility is deteriorating progressively with storage time, with only minor differences between drying methods, retaining enhanced dissolution rate. Crystal lattice simulations suggest high mechanical anisotropy of form I crystals, which could be an additional reason for fast particle size reduction prior to the polymorphic transformation. Wet media milling, combined with a suitable drying method, can be an efficient technique for the production of stable nanocrystals of agomelatine. Particle informatics methods can enhance our understanding of the mechanisms responsible for agomelatine's nanocomminution.

Potential application of low molecular weight excipients for amorphization and dissolution enhancement of carvedilol.

In this study, four low molecular weight (LMW) excipients, tryptophan (TRY), phenylalanine (PHE), lysine (LYS) and saccharin (SAC) were evaluated as co-formers to generate co-amorphous systems (CAMS) by ball milling with carvedilol (CRV). Mixtures of CRV and LMW excipient in 1:0.5, 1:1 and 1:2 drug:excipient molar ratios were ball milled and analysed by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform (FT-IR) infrared spectroscopy and dissolution testing. CAMS were formed by milling of a mixture of CRV with TRY in 1:2 M ratio and SAC in 1:1 M ratio, while amorphization of only CRV was achieved in other mixtures with SAC. In other samples containing TRY and PHE, milling resulted in partial amorphization, while LYS was the least suitable excipient for the amorphization of CRV. Unexpectedly, the highest supersaturation of CRV was achieved from samples containing CRV and LYS in 1:1 and 1:2 M ratios, despite the absence of a significant reduction in CRV crystallinity upon milling of these samples. Increase of hydrophobic surface area caused by milling of samples with TRY and PHE and agglomeration during dissolution testing of samples containing SAC are likely causes of poor dissolution performance of mixtures containing fully or partially amorphous CRV.

Co-Spray Drying of Paracetamol and Propyphenazone with Polymeric Binders for Enabling Compaction and Stability Improvement in a Combination Tablet.

Paracetamol (PCT) and propyphenazone (PRP) are analgesic drugs that are often combined in a single dosage form for enhanced pharmacological action. In this work, PCT and PRP were co-spray dried separately with hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) using drug suspensions in polymer solutions as feed liquids. It was thought that because of polymer adherence to the surface of drug particles, the risk of PCT-PRP contact and interaction could be reduced. Such interaction may be caused by localized temperature gradients due to frictional forces during tableting, or during storage under harsh conditions. A worst-case scenario would be eutectic formation due to variations in powder mixture homogeneity since eutectic and therapeutic mass PCT/PRP ratios are close (65:35 and 60:40, respectively) and eutectic temperature is low (~56 °C). Uniform particle size, round shape, compaction improvement and faster release of the analgesics were important additional benefits of co-spray drying. Experimental design was first applied for each drug to optimize the polymer concentration on the yield of spray drying and melting point separation (Δmp) of heated binary mixtures of co-spray dried PCT/neat PRP, and vice versa, with the two drugs always included at their therapeutic 60:40 ratio. Optimal combinations with largest Δmp and production yield were: co-spray dried PCT (15% HPC) with neat PRP and co-spray dried PRP (10% HPMC) with neat PCT. Compression studies of these combinations showed tableting improvement due to the polymers, as reflected in greater work of compaction and solid fraction, greater fracture toughness and tablet strength, easier tablet detachment from the punch surface and ejectability. Faster release of both drugs was obtained from the tablet of co-spray dried PCT (15% HPC) with neat PRP. A one-month stability test (75% RH/40 °C) showed moisture-induced alteration tablet strength.

Sildenafil 4.0-Integrated Synthetic Chemistry, Formulation and Analytical Strategies Effecting Immense Therapeutic and Societal Impact in the Fourth Industrial Era.

Sildenafil is a potent selective, reversible inhibitor of phosphodiesterase type 5 (PDE5) approved for the treatment of erectile dysfunction and pulmonary arterial hypertension. Whilst twenty years have passed since its original approval by the US Food and Drug Administration (USFDA), sildenafil enters the fourth industrial era catalyzing the treatment advances against erectile dysfunction and pulmonary hypertension. The plethora of detailed clinical data accumulated and the two sildenafil analogues marketed, namely tadalafil and vardenafil, signify the relevant therapeutic and commercial achievements. The pharmacokinetic and pharmacodynamic behavior of the drug appears complex, interdependent and of critical importance whereas the treatment of special population cohorts is considered. The diversity of the available formulation strategies and their compatible administration routes, extend from tablets to bolus suspensions and from per os to intravenous, respectively, inheriting the associated strengths and weaknesses. In this comprehensive review, we attempt to elucidate the multi-disciplinary elements spanning the knowledge fields of chemical synthesis, physicochemical properties, pharmacology, clinical applications, biopharmaceutical profile, formulation approaches for different routes of administration and analytical strategies, currently employed to guide the development of sildenafil-based compositions.

mRNA Therapeutic Modalities Design, Formulation and Manufacturing under Pharma 4.0 Principles.

In the quest for a formidable weapon against the SARS-CoV-2 pandemic, mRNA therapeutics have stolen the spotlight. mRNA vaccines are a prime example of the benefits of mRNA approaches towards a broad array of clinical entities and druggable targets. Amongst these benefits is the rapid cycle "from design to production" of an mRNA product compared to their peptide counterparts, the mutability of the production line should another target be chosen, the side-stepping of safety issues posed by DNA therapeutics being permanently integrated into the transfected cell's genome and the controlled precision over the translated peptides. Furthermore, mRNA applications are versatile: apart from vaccines it can be used as a replacement therapy, even to create chimeric antigen receptor T-cells or reprogram somatic cells. Still, the sudden global demand for mRNA has highlighted the shortcomings in its industrial production as well as its formulation, efficacy and applicability. Continuous, smart mRNA manufacturing 4.0 technologies have been recently proposed to address such challenges. In this work, we examine the lab and upscaled production of mRNA therapeutics, the mRNA modifications proposed that increase its efficacy and lower its immunogenicity, the vectors available for delivery and the stability considerations concerning long-term storage.

Overcoming the Solubility Barrier of Ibuprofen by the Rational Process Design of a Nanocrystal Formulation.

Wet media milling, coupled with spay drying, is a commonly proposed formulation strategy for the production and solidification of nanosuspensions in order to overcome the solubility barrier of BCS Class II substances. However, the application of mechanically and thermally intensive processes is not straightforward in the cases of ductile and/or low melting point substances that may additionally be susceptible to eutectic formation. Using ibuprofen (IBU) as a model drug with non-favorable mechanical and melting properties, we attempt to rationalize nanocrystal formulation and manufacturing in an integrated approach by implementing Quality by Design (QbD) methodology, particle informatics techniques and computationally assisted process design. Wet media milling was performed in the presence of different stabilizers and co-milling agents, and the nanosuspensions were solidified by spray-drying. The effects of key process parameters (bead diameter, milling time and rotational speed) and formulation variables (stabilizer type and drug/stabilizer ratio) on the critical quality attributes (CQAs), i.e., Z-average size, polydispersity index (PDI), ζ-potential and redispersibility of spray-dried nanosuspensions were evaluated, while possible correlations between IBU free surface energy and stabilizer effectiveness were studied. The fracture mechanism and surface stabilization of IBU were investigated by computer simulation of the molecular interactions at the crystal lattice level. As a further step, process design accounting for mass-energy balances and predictive thermodynamic models were constructed to scale-up and optimize the design space. Contemplating several limitations, our multilevel approach offers insights on the mechanistic pathway applicable to the substances featuring thermosensitivity and eutectic tendency.

Partially hydrolyzed polyvinyl alcohol for fusion-based pharmaceutical formulation processes: Evaluation of suitable plasticizers.

The present study evaluates the effect of several pharmaceutical plasticizers on the thermo-physical and physicochemical properties of partially hydrolyzed poly(vinyl alcohol) (PVA) used in fusion-based pharmaceutical formulation processes. Specifically, the effect of mannitol (MAN), sorbitol (SOR), sucrose (SUC), anhydrous citric acid (CA), triethyl citrate (TEC) and low-molecular weight polyethylene glycol (PEG400) on PVA's melting properties, physical state and thermal degradation was evaluated via differential scanning calorimetry (DSC), powder X-ray diffractometry (pXRD) and thermo-gravimetric analysis (TGA). Results showed that the use of MAN, SOR, SUC and PEG400 led to the reduction of PVA's melting onset temperature, while MAN, SUC, CA and SOR were amorphously dispersed within PVA's matrix, and the addition of SUC and CA resulted in significant reduction of PVA's crystallinity. TGA results showed the formation of thermally highly unstable PVA mixtures in the cases of CA and TEC (degradation started from ~150 °C and ~125 °C, respectively), while significant molecular interactions were identified by FTIR in the cases of PVA-MAN, PVA-SOR and PVA-SUC. Hot-stage polarized microscopy (HSM) revealed PVA's melt miscibility only with MAN and SOR, while melt flow index (MFI) measurements showed that the use of MAN, SOR and PEG400 resulted in a significant improvement of PVA's melt flow properties. Finally, MD simulations were in close agreement with the experimental observations, indicating that they can be considered as a promising tool for the theoretical modelling of such systems.

Crystallization tendency of APIs possessing different thermal and glass related properties in amorphous solid dispersions.

The correlation between glass forming ability (GFA) and several thermophysical or physicochemical properties of APIs with the formation and the physical stability of amorphous solid dispersions (ASDs) was evaluated in the present study. Eight poorly water-soluble APIs belonging in different GFA classes (i.e. a) GFA Class I: Carbamazepine, CBZ, b) GFA Class II: Agomelatine, AGO, Aprepitant, APT, Rivaroxaban, RIV, and c) GFA Class III: Indomethacin, IND, Pioglitazone, PIO, Piroxixam, PIR, and Simvastatin, SIM) were tested, in addition to six commonly used matrix-carriers (namely povidone, PVP, hydroxypropyl cellulose, HPC-SL, copovidone, coPVP, Soluplus®, SOL, and gelatin) in order to prepared ASDs via film casting approach. Results using polarized light microscopy (PLM) showed a similar drug crystallization tendency from ASDs independently of their GFA classification, glass stability or glass fragility. X-ray diffraction analysis verified the formation and the physical stability of ASD (independently of GFA class) when a suitable matrix-carrier was selected (i.e. SOL for AGO, RIV and SIM, PVP for APT, CBZ and IND, coPVP for PIO and gelatin for PIR). Further attempts to correlate some physicochemical properties (i.e. component's binding affinity and miscibility) with the formation and the crystallization tendency of the prepared ASDs showed no apparent correlation in regards to the different drug GFA classes. Finally, the evaluation of molecular interactions via FTIR analysis also failed to adequately distinguish the differences in regards to the formation and the physical stability of the prepared systems.

Insight into the Formation of Glimepiride Nanocrystals by Wet Media Milling.

Nanocrystal formation for the dissolution enhancement of glimepiride was attempted by wet media milling. Different stabilizers were tested and the obtained nanosuspensions were solidified by spray drying in presence of mannitol, and characterized regarding their redispersibility by dynamic light scattering, physicochemical properties by differential scanning calorimetry (DSC), FT-IR spectroscopy, powder X-ray diffraction (PXRD), and scanning electron microcopy (SEM), as well as dissolution rate. Lattice energy frameworks combined with topology analysis were used in order to gain insight into the mechanisms of particle fracture. It was found that nanosuspensions with narrow size distribution can be obtained in presence of poloxamer 188, HPC-SL and Pharmacoat® 603 stabilizers, with poloxamer giving poor redispersibility due to melting and sticking of nanocrystals during spray drying. DSC and FT-IR studies showed that glimepiride does not undergo polymorphic transformations during processing, and that the milling process induces changes in the hydrogen bonding patterns of glimepiride crystals. Lattice energy framework and topology analysis revealed the existence of a possible slip plane on the (101) surface, which was experimentally verified by PXRD analysis. Dissolution testing proved the superior performance of nanocrystals, and emphasized the important influence of the stabilizer on the dissolution rate of the nanocrystals.

Rivaroxaban polymeric amorphous solid dispersions: Moisture-induced thermodynamic phase behavior and intermolecular interactions.

The present study evaluates the physical stability and intermolecular interactions of Rivaroxaban (RXB) amorphous solid dispersions (ASDs) in polymeric carriers via thermodynamic modelling and molecular simulations. Specifically, the Flory-Huggins (FH) lattice solution theory was used to construct thermodynamic phase diagrams of RXB ASDs in four commonly used polymeric carriers (i.e. copovidone, coPVP, povidone, PVP, Soluplus, SOL and hypromellose acetate succinate, HPMCAS), which were stored under 0%, 60% and 75% relative humidity (RH) conditions. In order to verify the phase boundaries predicted by FH modelling (i.e. truly amorphous zone, amorphous-amorphous demixing zones and amorphous-API recrystallization zones), samples of ASDs were examined via polarized light microscopy after storage for up to six months at various RH conditions. Results showed a good agreement between the theoretical and the experimental approaches (i.e. coPVP and PVP resulted in less physically-stable ASDs compared to SOL and HPMCAS) indicating that the proposed FH-based modelling may be a useful tool in predicting long-term physical stability in high humidity conditions. In addition, molecular dynamics (MD) simulations were employed in order to interpret the observed differences in physical stability. Results, which were verified via differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR), suggested the formation of similar intermolecular interactions in all cases, indicating that the interaction with moisture water plays a more crucial role in ASD physical stability compared to the formation of intermolecular interactions between ASD components.

Analytical and Computational Methods for the Estimation of Drug-Polymer Solubility and Miscibility in Solid Dispersions Development.

The development of stable solid dispersion formulations that maintain desired improvement of drug dissolution rate during the entire shelf life requires the analysis of drug-polymer solubility and miscibility. Only if the drug concentration is below the solubility limit in the polymer, the physical stability of solid dispersions is guaranteed without risk for drug (re)crystallization. If the drug concentration is above the solubility, but below the miscibility limit, the system is stabilized through intimate drug-polymer mixing, with additional kinetic stabilization if stored sufficiently below the mixture glass transition temperature. Therefore, it is of particular importance to assess the drug-polymer solubility and miscibility, to select suitable formulation (a type of polymer and drug loading), manufacturing process, and storage conditions, with the aim to ensure physical stability during the product shelf life. Drug-polymer solubility and miscibility can be assessed using analytical methods, which can detect whether the system is single-phase or not. Thermodynamic modeling enables a mechanistic understanding of drug-polymer solubility and miscibility and identification of formulation compositions with the expected formation of the stable single-phase system. Advance molecular modeling and simulation techniques enable getting insight into interactions between the drug and polymer at the molecular level, which determine whether the single-phase system formation will occur or not.

Amorphous agomelatine stabilization in the presence of pyrogenic silica: Molecular mobility and intermolecular interaction studies.

In the present work molecular mobility and intermolecular interactions were evaluated as two distinct mechanisms for amorphous agomelatine (AGM) stabilization in the presence of pyrogenic silica. Specifically, amorphous AGM properties related to molecular mobility in terms of relaxation time were calculated based on the Kohlrausch-Williams-Watts (KWW) and Adam-Gibbs (AG) equations, while the kinetic fragility index was calculated based on temperature-modulated differential scanning calorimetry (TM-DSC). Results showed that independently of the approach followed (KWW or AG) AGM's molecular mobility was reduced in the presence of silica (KWW calculated stretched relaxation time constant, τß, was 83.61 and 44.78 for AGM and AGM/silica dispersions; respectively, while AG-based initial relaxation time, τ0, at storage temperatures 40-50 K below AGM's Tg was increased from six to eight days in the presence of silica); while kinetic fragility index values for amorphous AGM were reduced from 116.05 to 110.24 in the presence of silica. Additionally, MD simulations verified experimentally via attenuated total reflectance (ATR) FTIR spectroscopy, revealed the presence of significant intermolecular interactions between AGM and silica which act as an additional mechanism for amorphous AGM stabilization.

Molecular modelling and simulation of fusion-based amorphous drug dispersions in polymer/plasticizer blends.

A realistic molecular description of amorphous drug-polymer-plasticizer matrices, suitable for the preparation of amorphous solid dispersions (ASDs) with the aid of fusion-based techniques, was evaluated. Specifically, the incorporation of two model drugs (i.e. ibuprofen, IBU, and carbamazepine, CBZ) having substantially different thermal properties and glass forming ability, on the molecular representation of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOL)/polyethylene glycol (PEG, working as a plasticizer) molecular and thermal properties were evaluated with the aid of classical molecular dynamics (MD) and docking simulations. Results showed good agreement between molecular modelling estimations and experimentally determined properties. Specifically, the computed Tg values that resulted from MD simulations for IBU-SOL/PEG and CBZ-SOL/PEG (53.8 and 54.2 °C, respectively) were in reasonable agreement with the corresponding values resulting from differential scanning calorimetry (DSC) measurements (49.8 and 50.1 °C), while both molecular modelling and experimental obtained results suggested miscibility among system components. Additionally, interactions between CBZ and SOL observed during MD simulations were verified by FTIR analysis, while MD simulations of the hydration process suggested strong molecular interactions between IBU-SOL and CBZ-SOL.

Comparison of multi-linear regression, particle swarm optimization artificial neural networks and genetic programming in the development of mini-tablets.

In the present study, the preparation of pharmaceutical mini-tablets was attempted in the framework of Quality by Design (QbD) context, by comparing traditionally used multi-linear regression (MLR), with artificially-intelligence based regression techniques (such as standard artificial neural networks (ANNs), particle swarm optimization (PSO) ANNs and genetic programming (GP)) during Design of Experiment (DoE) implementation. Specifically, the effect of diluent type and particle size fraction for three commonly used direct compression diluents (lactose, pregelatinized starch and dibasic calcium phosphate dihydrate, DCPD) blended with either hydrophilic or hydrophobic flowing aids was evaluated in terms of: a) powder blend properties (such as bulk (Y1) and tapped (Y2) density, Carr's compressibility index (Y3, CCI), Kawakita's compaction fitting parameters a (Y4) and 1/b (Y5)), and b) mini-tablet's properties (such as relative density (Y6), average weight (Y7) and weight variation (Y8)). Results showed better flowing properties for pregelatinized starch and improved packing properties for lactose and DPCD. MLR analysis showed high goodness of fit for the Y1, Y2, Y4, Y6 and Y8 with RMSE values of Y1 = 0.028, Y2 = 0.032, Y4 = 0.019, Y6 = 0.015 and Y8 = 0.130; while for rest responses, high correlation was observed from both standard ANNs and GP. PSO-ANNs fitting was the only regression technique that was able to adequately fit all responses simultaneously (RMSE values of Y1 = 0.026, Y2 = 0.022, Y3 = 0.025, Y4 = 0.010, Y5 = 0.063, Y6 = 0.013, Y7 = 0.064 and Y8 = 0.104).

Co-Amorphous Solid Dispersions for Solubility and Absorption Improvement of Drugs: Composition, Preparation, Characterization and Formulations for Oral Delivery.

The amorphous solid state offers an improved apparent solubility and dissolution rate. However, due to thermodynamic instability and recrystallization tendencies during processing, storage and dissolution, their potential application is limited. For this reason, the production of amorphous drugs with adequate stability remains a major challenge and formulation strategies based on solid molecular dispersions are being exploited. Co-amorphous systems are a new formulation approach where the amorphous drug is stabilized through strong intermolecular interactions by a low molecular co-former. This review covers several topics applicable to co-amorphous drug delivery systems. In particular, it describes recent advances in the co-amorphous composition, preparation and solid-state characterization, as well as improvements of dissolution performance and absorption are detailed. Examples of drug-drug, drug-carboxylic acid and drug-amino acid co-amorphous dispersions interacting via hydrogen bonding, π-π interactions and ionic forces, are presented together with corresponding final dosage forms.

Molecular simulations for amorphous drug formulation: Polymeric matrix properties relevant to hot-melt extrusion.

In the present study molecular modelling was used to evaluate polymeric drug carrier matrix properties suitable for hot-melt extrusion (HME). Specifically, the effect of three commonly used plasticizers, namely, citric acid (CA), triethyl citrate (TEC) and polyethylene glycol (PEG), on Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, SOL) properties were evaluated with the aid of classical molecular dynamics (MD) and docking simulations. Differential scanning calorimetry (DSC) and ATR-FTIR spectroscopy of polymer-plasticizer mixtures were used to experimentally verify the in silico predictions. Computed Tg value by MD simulations for SOL was in reasonable agreement with the experimentally determined Tg value (72.0 vs. 69.4 °C, for MD and DSC measurement, respectively). Solubility parameter calculations with the aid of MD simulations along with calculated molecular lipophilicity potential interaction (MLPI) scores based on molecular docking, suggested component miscibility only in the case of SOL and PEG. This was verified by a positive deviation of the Tg values determined by DSC, compared to the Gordon-Taylor theoretical predictions. Additionally, the calculated MLPI scores suggested strong interactions between SOL and PEG, verified also by ATR-FTIR. Finally, MD simulations of the hydration process suggested strong hydrogen bonding between SOL - CA, and CA - water molecules.