Spray drying and hot-melt extrusion are among the most prevalent preparation techniques used in the pharmaceutical industry to produce amorphous solid dispersions (ASDs). This study advances previous research by integrating sample production, comprehensive analytical characterization, intrinsic dissolution rate measurements, and assessments of the behavior of ASDs under elevated temperature and humidity conditions. The study focuses on indomethacin, a widely used model for poorly soluble drugs, processed with PVP K30 or HPMC E5, both commonly used polymers. The findings demonstrate that hot-melt extruded samples exhibit superior stability against recrystallization, whereas spray dried samples achieve higher intrinsic dissolution rates. Furthermore, PVP K30 significantly outperforms HPMC E5 in the co-processing of indomethacin, enhancing both the intrinsic dissolution rate and the stability.

• Keywords
• Amorphous solid dispersions, Dissolution, Hot-melt extrusion, Recrystallization, Spray drying, Stability,
• MeSH
• Chemistry, Pharmaceutical methods   MeSH
• Indomethacin * chemistry   MeSH
• Crystallization MeSH
• Methylcellulose analogs & derivatives   chemistry   MeSH
• Povidone chemistry   MeSH
• Drug Compounding methods   MeSH
• Pyrrolidines chemistry   MeSH
• Solubility MeSH
• Spray Drying MeSH
• Drug Stability MeSH
• Hot Melt Extrusion Technology * methods   MeSH
• Drug Liberation MeSH
• Humidity MeSH
• Hot Temperature MeSH
• Desiccation MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Indomethacin * MeSH
• Methylcellulose MeSH
• Povidone MeSH
• Pyrrolidines MeSH

The integration of 3D printing into the pharmaceutical sciences opens new possibilities for personalized medicine. Poly(lactide) (PLA), a biodegradable and biocompatible polymer, is highly suitable for biomedical applications, particularly in the context of 3D printing. However, its processability often requires the addition of plasticizers. This study investigates the use of phase diagram modeling as a tool to guide the rational selection of plasticizers and to assess their impact on the thermodynamic and kinetic stability of PLA-based amorphous solid dispersions (ASDs) containing active pharmaceutical ingredients (APIs). Thermodynamic stability against API recrystallization was predicted based on the API solubility in PLA and Plasticizer-PLA carriers using the Conductor-like Screening Model for Real Solvents (COSMO-RS), while the kinetic stability of the ASDs was evaluated by modeling the glass transition temperatures of the mixtures. Two APIs, indomethacin (IND) and naproxen (NAP), with differing glass-forming abilities (i.e., recrystallization tendencies), and three plasticizers, triacetin (TA), triethyl citrate (TEC), and poly(L-lactide-co-caprolactone) (PLCL), were selected for investigation. The physical stability of ASD formulations containing 9 wt% API and plasticizer to PLA in two ratios, 10:81 and 20:71 w/w %, was monitored over time using differential scanning calorimetry and X-ray powder diffraction and compared with phase diagram predictions. All formulations were predicted to be thermodynamically unstable; however, those containing no plasticizer or with TEC and TA at 10 wt% were predicted to exhibit some degree of kinetic stability. Long-term physical studies corroborated these predictions. The correlation between the predicted phase behavior and long-term physical stability highlights the potential of phase diagram modeling as a tool for the rational design of ASDs in pharmaceutical 3D printing.

• Keywords
• 3D printing, Active pharmaceutical ingredient, Amorphous solid dispersion, COSMO-RS, PLA, Personalized medicine, Phase diagram, Plasticizers,
• MeSH
• Printing, Three-Dimensional * MeSH
• Citrates chemistry   MeSH
• Calorimetry, Differential Scanning methods   MeSH
• Chemistry, Pharmaceutical methods   MeSH
• Indomethacin chemistry   MeSH
• Kinetics MeSH
• Crystallization MeSH
• Naproxen chemistry   MeSH
• Polyesters * chemistry   MeSH
• Drug Compounding methods   MeSH
• Drug Design MeSH
• Solubility MeSH
• Drug Stability MeSH
• Thermodynamics MeSH
• Triacetin chemistry   MeSH
• Plasticizers chemistry   MeSH
• Phase Transition MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Citrates MeSH
• ethyl citrate MeSH Browser
• Indomethacin MeSH
• Naproxen MeSH
• poly(lactide) MeSH Browser
• Polyesters * MeSH
• Triacetin MeSH
• Plasticizers MeSH

The influence of partial crystallinity on the structural relaxation behavior of low-molecular organic glasses is, contrary to, e.g., polymeric materials, a largely unexplored territory. In the present study, differential scanning calorimetry was used to prepare a series of amorphous indomethacin powders crystallized to various extents. The preparations stemmed from the two distinct particle size fractions: 50-125 µm and 300-500 µm. The structural relaxation data from the cyclic calorimetric measurements were described in terms of the phenomenological Tool-Narayanaswamy-Moynihan model. For the 300-500 µm powder, the crystalline phase forming dominantly on the surface led to a monotonous decrease in the glass transition by ~6 °C in the 0-70% crystallinity range. The activation energy of the relaxation motions and the degree of heterogeneity within the relaxing matrix were not influenced by the increasing crystallinity, while the interconnectivity slightly increased. This behavior was attributed to the release of the quenched-in stresses and to the consequent slight increase in the structural interconnectivity. For the 50-125 µm powder, distinctly different relaxation dynamics were observed. This leads to a conclusion that the crystalline phase grows throughout the bulk glassy matrix along the internal micro-cracks. At higher crystallinity, a sharp increase in Tg, an increase in interconnectivity, and an increase in the variability of structural units engaged in the relaxation motions were observed.

• Keywords
• TNM model, crystallinity, indomethacin, structural relaxation,
• MeSH
• Calorimetry, Differential Scanning MeSH
• Indomethacin * chemistry   MeSH
• Crystallization MeSH
• Powders MeSH
• Temperature MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Indomethacin * MeSH
• Powders MeSH

Differential scanning calorimetry and Raman spectroscopy were used to study the nonisothermal and isothermal crystallization behavior of amorphous indomethacin powders (with particle sizes ranging from 50 to 1000 µm) and their dependence on long-term storage conditions, either 0-100 days stored freely at laboratory ambient temperatures and humidity or placed in a desiccator at 10 °C. Whereas the γ-form polymorph always dominated, the accelerated formation of the α-form was observed in situations of heightened mobility (higher temperature and heating rate), increased amounts of mechanically induced defects, and prolonged free-surface nucleation. A complex crystallization behavior with two separated crystal growth modes (originating from either the mechanical defects or the free surface) was identified both isothermally and nonisothermally. The diffusionless glass-crystal (GC) crystal growth was found to proceed during the long-term storage at 10 °C and zero humidity, at the rate of ~100 µm of the γ-form surface crystalline layer being formed in 100 days. Storage at the laboratory temperature (still below the glass transition temperature) and humidity led only to a negligible/nondetectable GC growth for the fine indomethacin powders (particle size below ~150 µm), indicating a marked suppression of GC growth by the high density of mechanical defects under these conditions. The freely stored bulk material with no mechanical damage and a smooth surface exhibited zero traces of GC growth (as confirmed by microscopy) after >150 days of storage. The accuracy of the kinetic predictions of the indomethacin crystallization behavior was rather poor due to the combined influences of the mechanical defects, competing nucleation, and crystal growth processes of the two polymorphic phases as well as the GC growth complex dependence on the storage conditions within the vicinity of the glass transition temperature. Performing paired isothermal and nonisothermal kinetic measurements is thus highly recommended in macroscopic crystallization studies of drugs with similarly complicated crystal growth behaviors.

• Keywords
• amorphous indomethacin, crystallization, kinetic prediction, particle size, storage,
• MeSH
• Calorimetry, Differential Scanning MeSH
• Indomethacin * chemistry   MeSH
• Crystallization MeSH
• Temperature MeSH
• Transition Temperature MeSH
• Particle Size MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Indomethacin * MeSH

The transdermal application of actives offers numerous advantages over other conventional routes. Namely, a stable level of drugs in the bloodstream and reduced side effects are the argument for topical administration. Unfortunately, the exceptional skin barrier and unsuitable physico-chemical properties of drugs are the limiting factors for the transdermal passage. It is possible to overcome this by incorporating the drug into nano-carriers to enhance its permeation through the skin barrier. For this purpose, we prepared lipid nanocapsules (LNCs) to modulate skin passage of three pharmaceutically important drugs - indomethacin (IND), diclofenac sodium (DF) and caffeine (CF). We present a stable system prepared by the phase inversion temperature method with particle size under 100 nm and PDI < 0.1 with great encapsulation efficiency for indomethacin and diclofenac. By FTIR it was possible to confirm (for IND and DF) or disprove (in case of CF) the incorporation of a drug into the LNCs. By ex vivo permeation experiments on porcine skin, we confirmed the superior effect of the LNCs on the APIs skin passage. The drug permeated through the skin with higher intensity when delivered from LNCs compared to other standard formulations. We show that lipid nanocapsules play an important role in enhanced topical application of actives.

• Keywords
• Caffeine, Dermal and transdermal delivery, Diclofenac, Indomethacin, Lipid nanocapsules,
• MeSH
• Administration, Cutaneous MeSH
• Diclofenac MeSH
• Indomethacin MeSH
• Lipids chemistry   MeSH
• Nanocapsules * chemistry   MeSH
• Drug Carriers chemistry   MeSH
• Particle Size MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Diclofenac MeSH
• Indomethacin MeSH
• Lipids MeSH
• Nanocapsules * MeSH
• Drug Carriers MeSH

Non-isothermal differential scanning calorimetry (DSC) was used to study the influences of particle size (daver) and heating rate (q+) on the structural relaxation, crystal growth and decomposition kinetics of amorphous indomethacin. The structural relaxation and decomposition processes exhibited daver-independent kinetics, with the q+ dependences based on the apparent activation energies of 342 and 106 kJ·mol-1, respectively. The DSC-measured crystal growth kinetics played a dominant role in the nucleation throughout the total macroscopic amorphous-to-crystalline transformation: the change from the zero-order to the autocatalytic mechanism with increasing q+, the significant alteration of kinetics, with the storage below the glass transition temperature, and the accelerated crystallization due to mechanically induced defects. Whereas slow q+ led to the formation of the thermodynamically stable γ polymorph, fast q+ produced a significant amount of the metastable α polymorph. Mutual correlations between the macroscopic and microscopic crystal growth processes, and between the viscous flow and structural relaxation motions, were discussed based on the values of the corresponding activation energies. Notably, this approach helped us to distinguish between particular crystal growth modes in the case of the powdered indomethacin materials. Ediger's decoupling parameter was used to quantify the relationship between the viscosity and crystal growth. The link between the cooperativity of structural domains, parameters of the Tool-Narayanaswamy-Moynihan relaxation model and microscopic crystal growth was proposed.

• Keywords
• DSC, amorphous indomethacin, crystal growth, particle size, structural relaxation, viscous flow,
• MeSH
• Calorimetry, Differential Scanning MeSH
• Indomethacin * chemistry   MeSH
• Crystallization MeSH
• Temperature MeSH
• Transition Temperature MeSH
• Viscosity MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Indomethacin * MeSH

In the presence of carboxypeptidase, the hydrolytically stable complex [Os(η6-pcym)(L2)Cl]PF6 (2) partially released the bioactive substituent indomethacin, bound through the amide bond to the chelating 2-(1,3,4-thiadiazol-2-yl)pyridine-based moiety of L2. Stability in the presence of other relevant biomolecules (GSH, NADH, GMP) and cancer cell viability were also studied.

• MeSH
• Indomethacin pharmacology   MeSH
• Carboxypeptidases A MeSH
• Coordination Complexes * chemistry   pharmacology   MeSH
• Ligands MeSH
• Cell Line, Tumor MeSH
• Antineoplastic Agents * chemistry   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Indomethacin MeSH
• Carboxypeptidases A MeSH
• Coordination Complexes * MeSH
• Ligands MeSH
• Antineoplastic Agents * MeSH

Commonly applied approaches to enhance the dissolution properties of low water-soluble crystalline active pharmaceutical ingredients (APIs) include their amorphization by incorporation into a polymeric matrix and the formation of amorphous solid dispersions, or blending APIs with low-molecular-weight excipients and the formation of a co-amorphous system. This study focused on the preparation and characterization of binary (consisting of indomethacin (IND) and polymer - copovidone (PVP VA 64), as a carrier, or amino acid - L-arginine (ARG), as a co-former) and ternary (comprising the same API, polymer, and amino acid) formulations. Formulations were produced by ball milling (BM) and/or hot-melt extrusion (HME), and extensive physicochemical characterization was performed. Specifically, the physicochemical and solid-state properties of a model IND-ARG system incorporated into a polymeric matrix of PVP VA 64 by HME and BM as well as by combined BM/HME method together with the impact of the preparation strategy on the dissolution profiles and long-term physical stability were investigated. Ball-milled binary and ternary formulations were found to be amorphous. The residual crystals corresponding to IND-ARG salt were identified in the ternary formulations produced via HME. Despite the presence of a crystalline phase, dissolution tests showed that ternary systems prepared by HME exhibited improved IND solubility when compared to pure crystalline IND and their corresponding physical mixture. None of the binary and ternary formulations that were initially fully amorphous did undergo recrystallization during the entire period of preservation (minimum of 12 months) in dry conditions at 25 °C.

• Keywords
• Amorphous solid dispersion, Co-amorphous, Dissolution performance, Physical stability, Solubility, Ternary formulation,
• MeSH
• Arginine * MeSH
• Indomethacin * MeSH
• Polymers MeSH
• Solubility MeSH
• Vinyl Compounds MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Arginine * MeSH
• Indomethacin * MeSH
• Polymers MeSH
• vinyl acetate MeSH Browser
• Vinyl Compounds MeSH

In drug development, preformulation is the key step, where compatibility between active pharmaceutical ingredient (API) and excipients is the crucial parameter. To simplify this process, reliable and suitable prediction models are needed. In this case, Hansen solubility parameters (HSPs) can be used. Moreover, HSPs can also describe and characterize the surface properties of the measured substances. Precisely, the surface properties of APIs and excipients affect the compatibility of the resulting dosage form. In this work, HSPs of six selected APIs of different chemical nature were determined (tadalafil, vardenafil-hydrochloride trihydrate, mefenamic acid, bisoprolol hemi-fumarate, meloxicam and indomethacin) using inverse gas chromatography (IGC) according to Snyder and Karger adsorption model. This study aimed to investigate the influence of APIs structure on HSPs and to prove the sensitivity of this method to different chemical nature of measured substances. Our results showed the influence of selected APIs chemical nature on HSPs. These results can provide a better understanding of API behaviour during the drug development process.

• Keywords
• Compatibility, Energy of adsorption, Hansen solubility parameters, Inverse gas chromatography, Snyder and Karger adsorption model, van Krevelen,
• MeSH
• Chromatography, Gas MeSH
• Indomethacin * MeSH
• Excipients * MeSH
• Surface Properties MeSH
• Solubility MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Indomethacin * MeSH
• Excipients * MeSH

Co-milling of a drug with a co-former is an efficient technique to improve the solubility of drugs. Besides the particle size reduction, the co-milling process induces a structural disorder and the creation of amorphous regions. The extent of drug solubility enhancement is dependent on the proper choice of co-milling co-former. The aim of this work was to compare the effects of different co-formers (meglumine and polyvinylpyrrolidone) on the dissolution rates of glass forming (indomethacin) and non-glass forming (mefenamic acid) model drugs. A positive impact of the co-milling on the dissolution behavior was observed in all co-milled mixtures, even if no substantial amorphization was observed. While meglumine exhibited pronounced effects on the dissolution rate of both drugs, the slightest enhancement was observed in mixtures with polyvinylpyrrolidone. The evaluation of specific release rate revealed the surface activation of drug particle is responsible for improving the dissolution rate of both drug types, but for the glass former, this surface activation could be persistent while maintaining a high dissolution rate even until a high fraction of drug is released. Our results, therefore, indicate that adequate co-former choice and consideration of drug glass forming ability are important for a successful co-milling approach to poorly water-soluble drugs.

• Keywords
• Co-milling, Dissolution rate, Glass forming ability, Indomethacin, Mefenamic acid,
• MeSH
• Indomethacin MeSH
• Pharmaceutical Preparations * MeSH
• Povidone * MeSH
• Drug Compounding MeSH
• Solubility MeSH
• Particle Size MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Indomethacin MeSH
• Pharmaceutical Preparations * MeSH
• Povidone * MeSH