Variations in the inner core affect the pharmacokinetics of indomethacin-encapsulated polymeric micelles.

Hydrophobic ion pairing (HIP) is a drug encapsulation technology that uses electrostatic interactions between a drug and an additive. However, although polymeric micelles can encapsulate hydrophobic drugs in the core, the encapsulated drug often leaks. Therefore, we designed polymeric micelles with HIP functionalized in a hydrophobic inner core using three diblock copolymers comprising polypeptides with different ratios of polar and hydrophobic amino acids and polyethylene glycol (PEG) to encapsulate indomethacin (IND). The three IND-encapsulated HIP micelles showed different area under the curve (AUC) values as an index of blood retention after intravenous injection in mice. Despite having the same PEG shell, IND-PEG-poly(H/F)n showed a 1.56-fold higher AUC than IND-PEG-poly(D/F)n. PEG interface morphologies were evaluated to determine the differences in pharmacokinetic parameters caused by changes in inner core HIP patterns. The micellarized diblock copolymer was desorbed from IND-PEG-poly(D/F)n due to electrostatic repulsion between IND and the diblock copolymer comprising aspartic acid. Our results suggest that changes in the HIP patterns of the micelle inner core affected the PEG interface morphologies, such as PEG density and diblock copolymer desorption from micelles. These phenomena might lead to changes in the interaction of plasma proteins and drug dispositions.

Small molecules modified mesoporous silica nanoparticles orally deliver indomethacin with synergistic effect.

Molecularly functional drug delivery systems possessed huge potentials to realize novel drug administration. To explore small molecules modified drug delivery, a series of small molecules modified mesoporous silica nanoparticles (L-Mal-MSNs, D-Mal-MSNs) were established by grafting small molecules. Poorly water-soluble indomethacin (IMC) was chosen to load into these small molecules modified carriers as well as corresponding control carrier, and further to study characteristics and delivery effects of drug loaded carriers. The results indicated that all these small molecules modified carriers formed hydrogen bonds with drugs and can successfully convert drug crystal phase to amorphous state so as to enhance drug dissolution compared to raw drug. In vivo rat intestinal perfusion demonstrated that IMC loaded L-Mal-MSNs performed the fastest drug absorption while analgesic and anti-inflammatory effects of IMC loaded D-Mal-MSNs turned out to be the best, giving hints that D-malic acid exhibited best synergic functions for IMC. The herein small molecules modified delivery system is an effective solution strategy for the current application of analgesia and anti-inflammatory drugs with outstanding significance.

Indomethacin-omeprazole as therapeutic hybrids? Salt and co-amorphous systems enhancing physicochemical and pharmacological properties.

Multidrug therapeutic hybrids constitute a promising proposal to overcome problems associated with traditional formulations containing physical mixtures of drugs, potentially improving pharmacological and pharmaceutical performance. Indomethacin (IND) is a non-selective non-steroidal anti-inflammatory drug (NSAIDs) that acts by inhibiting normal processes of homeostasis, causing a series of side effects, such as gastrointestinal symptoms. Proton pump inhibitors, such as omeprazole (OME), have been used to treat such gastrointestinal tract symptoms. In this work, two new multidrug therapeutic hybrids were prepared (an IND:OME salt and an IND:OME co-amorphous system) by ball mill grinding crystalline IND and OME under different conditions, i.e., liquid assisted grinding (LAG) with ethanol and dry grinding, respectively. The crystalline salt returned to a neutral state co-amorphous system when submitted to ball mill grinding in the absence of solvent (dry grinding), but the reverse process (LAG of the IND:OME co-amorphous system) showed partial decomposition of OME. The IND:OME co-amorphous system showed a higher physical stability than the neat IND and OME amorphous materials (with an amorphous stability longer than 100 days, compared to 4 and 16 h for the neat amorphous drugs, respectively, when stored at dry conditions at room temperature). Furthermore, OME presented a higher chemical stability in solution when dissolved from a salt form than from the pure crystalline form. The dissolution studies showed a dissolution enhancement for IND in both salt (1.8-fold after 8 h of dissolution) and co-amorphous (2.5-fold after 8 h of dissolution) forms. Anti-inflammatory activity using a mice paw oedema model showed an increase of the pharmacological response to IND at a lower dose (∼5mg/kg) for both IND:OME salt (2.8-fold) and IND:OME co-amorphous system (3.2-fold) after 6 h, when compared to the positive control group (IND, administered at 10 mg/kg). Additionally, the anti-inflammatory activity of both salt and co-amorphous form was faster than for the crystalline IND. Finally, an indomethacin-induced gastric ulceration assay in mice resulted in a higher mucosal protection at the same dose (40 mg/kg) for both IND:OME salt and IND:OME co-amorphous system when compared with crystalline OME.

Analysis of stabilization mechanisms in ß-lactoglobulin-based amorphous solid dispersions by experimental and computational approaches.

Our previous work shows that ß-lactoglobulin-stabilized amorphous solid dispersion (ASD) loaded with 70 % indomethacin remains stable for more than 12 months. The stability is probably due to hydrogen bond networks spread throughout the ASD, facilitated by the indomethacin which has both hydrogen donors and acceptors. To investigate the stabilization mechanisms further, here we tested five other drug molecules, including two without any hydrogen bond donors. A combination of experimental techniques (differential scanning calorimetry, X-ray power diffraction) and molecular dynamics simulations was used to find the maximum drug loadings for ASDs with furosemide, griseofulvin, ibuprofen, ketoconazole and rifaximin. This approach revealed the underlying stabilization factors and the capacity of computer simulations to predict ASD stability. We searched the ASD models for crystalline patterns, and analyzed diffusivity of the drug molecules and hydrogen bond formation. ASDs loaded with rifaximin and ketoconazole remained stable for at least 12 months, even at 90 % drug loading, whereas stable drug loadings for furosemide, griseofulvin and ibuprofen were at a maximum of 70, 50 and 40 %, respectively. Steric confinement and hydrogen bonding to the proteins were the most important stabilization mechanisms at low drug loadings (≤ 40 %). Inter-drug hydrogen bond networks (including those with induced donors), ionic interactions, and a high Tg of the drug molecule were additional factors stabilizing the ASDs at drug loading greater than 40 %.

Use of Time-Domain NMR for 1H T1 Relaxation Measurement and Fitting Analysis in Homogeneity Evaluation of Amorphous Solid Dispersion.

This study examined the usefulness of 1H T1 relaxation measurements for evaluating the homogeneity of amorphous solid dispersion (ASD). Indomethacin and polyvinylpyrrolidone were used to prepare two kinds of ASDs. One was inhomogeneous ASD (ASDmelt) prepared by a melt-quenching method, and the other was homogeneous ASD (ASDsolvent) prepared by a solvent evaporation method. The T1 relaxation was measured by the time-domain NMR (TD-NMR) technique using a low-field NMR system. Curve-fitting analysis of T1 relaxation plots was conducted using the Akaike information criterion. This fitting analysis revealed that the T1 relaxation of ASDmelt and ASDsolvent was biphasic and monophasic, respectively. ASDmelt and ASDsolvent were inhomogeneous and homogeneous on a nanometer scale, respectively, considering the spin diffusion of 1H nuclei. These T1 results were consistent with the Raman mapping of ASDs. From the fitting analysis of 1H T1 relaxation, we conclude that TD-NMR is a promising technique for evaluating ASD homogeneity.

Determination of the Solid Content of Active Pharmaceutical Ingredient Powders in Suspension-Type Pharmaceutical Oral Jelly Using Time-Domain NMR.

This study determined the content of solid active pharmaceutical ingredient (API) powders dispersed in suspension-type pharmaceutical oral jellies using a low-field time-domain NMR (TD-NMR). The suspended jellies containing a designated API content were prepared and tested. Acetaminophen (APAP), indomethacin (IMC) and L-valine were used as test APIs. First, this study measured the T2 relaxation rate (the reciprocal of T2 relaxation time) by the Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence, and then evaluated whether the API content could be determined by the acquired T2 relaxation rate. The T2 relaxation rate negatively correlated with API content to a certain extent, but their correlation was not sufficient for achieving a precise determination. Subsequently, the solid-echo pulse sequence measurement was adopted for this study. We found that NMR signals corresponding to solid components strongly correlated with API content. Thus, this method achieved a precise determination of API contents in suspended jellies. In addition, this study confirmed the effect of API particle size on the T2 relaxation rate by using an L-valine-containing jelly: the T2 relaxation rate became faster when a smaller API size was incorporated into the suspended jelly, while there was no difference in terms of the NMR signals measured by solid-echo pulse sequence. From these findings, TD-NMR could be a powerful tool for evaluating the API dispersion state in suspended oral jellies.

How the Presence of Crystalline Phase Affects Structural Relaxation in Molecular Liquids: The Case of Amorphous Indomethacin.

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.

Supramolecular nanofiber of indomethacin derivative confers highly cyclooxygenase-2 (COX-2) selectivity and boosts anti-inflammatory efficacy.

Herein, we report a facile method for converting carboxylate-containing indomethacin (Idm) into a cyclooxygenase-2 (COX-2) selective inhibitor via the amidation of an unnatural peptide sequence (Nal-Nal-Asp). The resulting indomethacin amides (i.e., Idm-Nal-Nal-Asp) have high selectivity for COX-2, and can self-assemble into a one-component supramolecular hydrogel that acts as a 'self-delivery' system for boosting anti-inflammatory efficacy. Self-assembled Idm-Nal-Nal-Asp hydrogel robustly inhibits COX-2 expression in lipopolysaccharide (LPS)-activated Raw 264.7 macrophages while also exhibits superior anti-inflammatory and antioxidant activities via reactive oxygen species (ROS)-related NF-κB and Nrf2/HO-1 pathways. Moreover, a rabbit model of endotoxin-induced uveitis (EIU) reveals that the Idm-Nal-Nal-Asp hydrogel outperforms clinically used 0.1 wt% diclofenac sodium eye drops in terms of in vivo anti-inflammatory efficacy via topical instillation route. As a rational approach to designing and applying COX-2 selective inhibitors, this work presents a simple method for converting non-selective nonsteriodal anti-inflammatory drugs (NSAIDs) into highly selective COX-2 inhibitors that can self-assemble into supramolecular hydrogel for anti-inflammation applications.

Mechanisms of Drug Solubility Enhancement Induced by ß-Lactoglobulin-Based Amorphous Solid Dispersions.

Protein-based amorphous solid dispersions (ASDs) have emerged as a promising approach for enhancing solubility in comparison to crystalline drugs. The dissolution behavior of protein-based amorphous solid dispersions (ASDs) was investigated in various pH media. ASDs of four poorly soluble model drugs with acidic (furosemide and indomethacin), basic (carvedilol), and neutral (celecoxib) properties were prepared by spray drying at 30 wt % drug loading with the protein ß-lactoglobulin (BLG). The effect of spray-dried BLG (SD-BLG) solubility and protein binding ability with dissolved drugs in solution were investigated to retrieve the mechanisms governing the improvement of drug solubility from the BLG-based ASDs. Powder dissolution results showed that all ASDs obtained a higher maximum concentration (Cmax) compared to the respective pure crystalline drugs. It was found that the solubility increase of the drugs from the ASDs was to a large extent dependent on the solubility of the pure SD-BLG at the investigated pH values (low solubility at pH near the isoelectric point (pI) of BLG). Furthermore, drug-protein interactions in a solution were observed, in particular at pH values where the drugs were neutral. These drug-protein interactions also resulted, to some extent, in the stabilization of the drug in supersaturation.

Non-salt based co-amorphous formulation produced by freeze-drying.

Amino acids-based co-amorphous system (CAM) has shown to be a promising approach to overcome the dissolution challenge of biopharmaceutics classification system class II drugs. To date, most CAM formulations are based on salt formation at a 1:1 M ratio and are prepared by mechanical activation. However, its use in medicinal products is still limited due to the lack of in-depth understanding of non-ionic based molecular interactions. There are also limited studies on the effect of drug-to-co-former ratio, the development of more scalable, less aggressive, manufacturing processes such as freeze drying and its dissolution benefits. This work aims to investigate the effect of the ratio of tryptophan (a model non-ionic amino acid) to indomethacin (a model drug) on a non-salt-based CAM prepared via freeze-drying with the tert-butyl alcohol-water cosolvent system. The CAM material was systemically characterized at various stages of the freeze-drying process using DSC, UV-Vis, FT-IR, NMR, TGA and XRPD. Dissolution performance and physical stability upon storage were also investigated. Freeze-drying using the cosolvent system has been successfully shown to produce CAMs. The molecular interactions involving H-bonding, H/π and π-π between compounds have been confirmed by FT-IR and NMR. The drug release rate for formulations with a 1.5:1 drug: amino acid molar ratio (or 1:0.42 wt ratio) or below is found to be significantly improved compared to the pure crystalline drug. Furthermore, formulation with a 2.3:1 drug:amino acid molar ratio (or 1:0.25 wt ratio) or below have shown to be physically stable for at least 9 months when stored at dry condition (5% relative humidity, 25 °C) compared to the pure amorphous indomethacin. We have demonstrated the potential of freeze-drying using tert-butyl alcohol-water cosolvent system to produce an optimal non-salt-based class II drug-amino acid CAM.

Effect of Structurally Related Compounds on Desupersaturation Kinetics of Indomethacin.

PURPOSE: The pharmaceutical literature contains examples wherein desupersaturation from high concentrations does not proceed to equilibrium concentration of the thermodynamically most stable form but remains above equilibrium. The purpose of the current research was to investigate the effect of structurally related compounds on desupersaturation kinetics as a possible explanation for a higher than equilibrium solubility after crystal growth of γ-indomethacin (γ-IMC). METHODS: Three structurally related compounds (SRC) - cis-sulindac (c-SUL), trans-sulindac (t-SUL) and indomethacin-related compound-A (IMC-A) -were investigated. Desupersaturation kinetics to the most stable γ-IMC, in the presence of c-SUL, t-SUL or IMC-A, was measured at pH 2.0. RESULTS: The SRCs c-SUL and t-SUL were effective crystallization inhibitors of IMC, while IMC-A was not a potent crystallization inhibitor of IMC. Among the sulindac isomers, t-SUL was a stronger crystallization inhibitor. The apparent solubility of γ-IMC crystals grown from supersaturated solutions in the presence of SRCs matched the equilibrium solubility of γ-IMC. During crystallization of IMC in the presence of IMC-A, the concentration of IMC-A declined initially but rebounded as supersaturation and crystallization rate of IMC declined, suggesting that IMC-A itself became incorporated in the IMC crystal lattice at higher degrees of IMC supersaturation. CONCLUSIONS: The results suggest that high apparent solubility after crystallization of IMC reported by several authors is not related to the presence of IMC-A impurity. The greater IMC crystal growth rate inhibition by t-SUL than by c-SUL was consistent with the proposed orientation of SUL molecules adsorbed on the IMC crystal, providing a mechanistic understanding of the inhibition.

Wet granulation of co-amorphous indomethacin systems.

The feasibility of co-amorphous systems to be wet granulated together with microcrystalline cellulose (MCC) was investigated. Solid state and molecular interactions were analysed for various co-amorphous drug-amino acid formulations of indomethacin with tryptophan and arginine, respectively, via XRPD, DSC and FTIR. The co-amorphous binary systems were produced by ball-milling for 90 min at different molar ratios followed by wet granulation with MCC and water in a miniaturised scale. Tryptophan containing systems showed crystalline reflections in their XRPD diffractograms and endothermal events in their DSC analyses, and were therefore excluded from upscaling attempts. The systems containing arginine were found to be remain amorphous for at least ten months and were upscaled for production in a high-shear blender under application of two different parameter settings. Under the harsher instrument settings, a composition with a low MCC ratio experienced recrystallisation during wet granulation, while all other compositions could be successfully processed via wet granulation and stayed stable for a storage period of at least twelve weeks, indicating that wet granulation of co-amorphous systems can be feasible.

Continuous Monitoring of the Agglomeration and Sedimentation of Indomethacin Nanosuspensions Using T2 Relaxation Time with Time-Domain NMR.

The time-domain NMR technique was utilized to monitor precisely the physicochemical stability of indomethacin (IMC) nanosuspensions using T2 relaxation time (T2). We investigated whether T2 values can distinguish between agglomeration and sedimentation. Nanosuspensions of IMC were prepared using aqueous wet bead milling with polyvinylpyrrolidone as a stabilizer. Prepared nanosuspensions were divided into two fractions: one was stored in the NMR equipment for continuous T2 measurements and the other was stored in the dispersion analyzer. Measurements of both nanosuspensions were carried out, without dilution, over a period of 24 h at 10-min intervals. Transmission profiles based on multilight scattering technology showed that agglomeration predominantly occurred at 25 and 35 °C immediately after wet bead milling up to 4 h, followed by sedimentation from 4 to 24 h. Upon measuring the T2 relaxation, T2 values at both 25 and 35 °C showed a two-step change-there was a significant prolongation in T2 values immediately after preparation of nanosuspensions up to approx. 4 h and a gradual prolongation in T2 values from approx. 4 to 24 h. Considering the results of transmission profiles, these two-step T2 changes correspond to agglomeration and sedimentation. In other words, this study established that monitoring the T2 values of nanosuspensions could be used to evaluate the agglomeration and sedimentation of contained drug particles. This technique does not directly observe the nanoparticles themselves, but the water molecules. Thus, measurement of T2 relaxation is considered to be a general-purpose technique, independent of the type of drug or polymer.

Development and characterization of crosslinked k-carrageenan/sericin blend with covalent agents or thermal crosslink for indomethacin extended release.

Modified release of multiparticulate pharmaceutical forms is a key therapeutic strategy to reduce side effects and toxicity caused by high and repeated doses of immediate-release oral drugs. This research focused on the encapsulation of indomethacin (IND) in the crosslinked k-Car/Ser polymeric matrix by covalent and thermal methods to evaluate drug delivery modulation and properties of the crosslinked blend. Therefore, the entrapment efficiency (EE %), drug loading (DL %) and physicochemical properties of the particles were investigated. The particles presented a spherical shape and a rough surface with a mean diameter of 1.38-2.15 mm (CCA) and 1.56-1.86 mm (thermal crosslink). FTIR investigation indicated the presence of IDM in the particles and X-ray pattern showed the maintenance of crystallinity of IDM. The in vitro release in acidic medium (pH 1.2) and phosphate buffer saline solution (pH 6.8) was 1.23-6.81 % and 81-100 %, respectively. Considering the results, the formulations remained stable after 6 months. The Weibull equation was adequately fitted for all formulations and a diffusion mechanism, swelling and relaxation of chain were observed. IDM-loaded k-carrageenan/sericin/CMC increases cell viability (> 75 % for neutral red and > 81 % for MTT). Finally, all formulations present gastro-resistance, pH response and altered release and have the potential to be used as drug delivery careers.

The Influence of Gastrointestinal Biomolecules on Solid-State Transformations in Pharmaceutical Particulates.

Adsorption of gut relevant biomolecules onto particles after oral administration of solid oral dosage forms is expected to form a "gastrointestinal corona", which could influence solution-mediated solid-state transformations on exposure of drug particles to gastrointestinal fluids. Low-frequency Raman (LFR) spectroscopy was used in this study to investigate in situ solid-state phase transformations under biorelevant temperature and pH conditions along with the presence of biomolecules. Melt-quenched amorphous indomethacin was used as a model solid particulate, and its solid-state behavior was evaluated at 37 °C and pH 1.2-6.8 with or without the presence of typical bile salt/phospholipid mixtures emulating fed-state conditions. Overall, a change in the solid-state transformation pathway from amorphous to crystalline drug was observed, where an intermediate ε-form that initially formed at pH 6.8 was suppressed by the addition of endogenous gastrointestinal biomolecules. These solid-state changes were corroborated using time-resolved synchrotron small- and wide-angle X-ray scattering (SAXS/WAXS). Additionally, the bile salt and phospholipid mixture partly prevented the otherwise strong aggregation between drug particles at more acidic conditions (pH ≤ 4.5) and helped to shift the balance against the intrinsic hydrophobicity of indomethacin as well as the plasticization effect brought about by the physiological temperature (i.e., the stickiness arising from the supercooled liquid state at 37 °C). The overall results highlight the importance of evaluating the impact that endogenous biomolecules may have on the solid-state characteristics of drug molecules in dissolution media, where analytical tools such as LFR spectroscopy can serve as an attractive avenue for accessing time-resolved solid-state information on time-scales that are difficult to achieve with other techniques such as X-ray diffraction.

Rapid Indomethacin Release from Porous Pectin Particles as a Colon-Targeted Drug Delivery System.

The conventional pectin delivery systems in the colon are often impaired by a slow release rate. Nanostructured particles, especially porous ones, have gained popularity as drug delivery systems owing to their high mass transfer efficiency. In this research, porous pectin particles were synthesized as drug carriers (using indomethacin as a model drug) via template-assisted spray drying. Specific surface areas of the porous pectin particles have been improved by up to 203 m2 g-1 compared with nonporous particles (1 m2 g-1). The porous structure shortened the diffusion path and improved the release rate of drug molecules. Additionally, the predominant drug release mechanism from porous pectin particles is Fickian diffusion, which is different from the combination of erosion and diffusion mechanism observed for nonporous particles. As a result, these porous drug-loaded pectin particles demonstrated rapid drug release rates of up to three times faster than nonporous particles. Control of the release rate could be achieved by changing the porous structure of the particles. This strategy is an efficient means to synthesize porous particles allowing rapid drug release into the colonic target.

Amorphous solid dispersions in high-swelling, low-substituted hydroxypropyl cellulose for enhancing the delivery of poorly soluble drugs.

Amorphous solid dispersions (ASDs) based on water-insoluble hydrophilic polymers can sustain supersaturation in their kinetic solubility profiles (KSPs) compared to soluble carriers. However, in the limit of very high swelling capacity, the achievable extent of drug supersaturation has not been fully examined. This study explores the limiting supersaturation behavior of ASDs of poorly soluble indomethacin (IND) and posaconazole (PCZ) based on a high-swelling excipient, low-substituted hydroxypropyl cellulose (L-HPC). Using IND as a reference, we showed that the rapid initial supersaturation buildup in the KSP of IND ASD can be simulated through sequential IND infusion steps, however at large times the KSP of IND release from ASD appears more sustained than direct IND infusion. This has been attributed to potential trapping of seed crystals generated in the L-HPC gel matrix thus limiting their growth and rate of desupersaturation. Similar result is also expected in PCZ ASD. Furthermore, the current drug loading process for ASD preparation resulted in the agglomeration of L-HPC based ASD particles, producing granules of up to 300-500 µm (cf. 20 µm individual particle), with distinct kinetic solubility profiles. This feature makes L-HPC particularly suitable as ASD carriers for fine tuning of supersaturation to achieve enhanced bioavailability for poorly soluble drugs.

Switch between Cocrystal and Coamorphous Forms Depending on Thermal Modulation of Hot-Melt Extrusion.

Cocrystal (CC) and coamorphous (CM) techniques have become green technologies to improve the solubility and bioavailability of water-soluble drugs. In this study, hot-melt extrusion (HME) was employed to produce CC and CM formulations of indomethacin (IMC) and nicotinamide (NIC) due to its advantages like solvent-free and large-scale manufacturing. Interestingly, for the first time, IMC-NIC CC and CM were selectively prepared depending on the barrel temperatures of HME at a constant screw speed of 20 rpm and a feed rate of 1.0 g/min. IMC-NIC CC was obtained at 105-120 °C, IMC-NIC CM was produced at 125-150 °C, and the mixture of CC and CM was obtained between 120 and 125 °C (like a door switch of CC and CM). SS NMR combined with RDF and Ebind calculations revealed the formation mechanisms of CC and CM, where strong interactions between heteromeric molecules formed at lower temperatures favored periodic molecular organization of CC, whereas discrete and weak interactions formed at higher temperatures promoted disordered molecular arrangement of CM. Additionally, IMC-NIC CC and CM showed enhanced dissolution and stability over crystalline/amorphous IMC. This study provides an easy-to-operate and environmentally friendly strategy for the flexible regulation of CC and CM formulations with different properties through modulation of the barrel temperature of HME.

Controlled release of a non-steroidal anti-inflammatory drug from a photocurable polymeric calcium phosphate cement.

In this research, a photocurable composite based on tetracalcuim phosphate ceramic and, hydroxyethyl methacrylate-modified poly(acrylic-maleic acid) was developed and studied as a potential drug delivery system for bone defects. Different concentrations (5, 10 and 20 wt. %) of a non-steroidal anti-inflammatory drug, Indomethacin, were loaded on to the composite and its release behavior was investigated in phosphate buffered solution during 504 h. The obtained release data were fitted by both power law (Peppas) and Weibull equations. The composites were also characterized after different soaking periods using X-ray diffractometry (XRD), scanning electron microscopy (SEM) and Fourier transforming infrared spectroscopy. The results of XRD and SEM analyses revealed the formation of nanosized needle/flake-like apatite crystals on the composites surfaces; however, better apatite formation was observed for the composites loaded with higher amounts of Indomethacin. The morphological observations and quantitative estimations revealed that the loaded composites were gradually degraded in the phosphate-buffered saline. Moreover, a controlled release of Indomethacin was found from the composites in which a higher drug concentration led to a more drug level as well as sustained release profile. In drug release modeling, better regression coefficient was obtained from the Weibull equation, compared to the power law, meaning that the Weibull equation suggests a better description of the indomethacin release from the composites during the whole period of the test. In conclusion, the photocurable composite with apatite formation ability can be successfully used for the controlled release of indomethacin as an anti-inflammatory drug in bone defects.

Indomethacin: Effect of Diffusionless Crystal Growth on Thermal Stability during Long-Term Storage.

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.