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. Di erent 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 di erential scanning calorimetry (DSC), FT-IR spectroscopy, powder X-ray di raction (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

Improvement of Aripiprazole Solubility by Complexation with (2-Hydroxy)propyl-beta-cyclodextrin Using Spray Drying Technique

Due to the fact that the number of new poorly soluble active pharmaceutical ingredients is increasing, it is important to investigate the possibilities of improvement of their solubility in order to obtain a final pharmaceutical formulation with enhanced bioavailability. One of the strategies to increase drug solubility is the inclusion of the APIs in cyclodextrins. The aim of this study was to investigate the possibility of aripiprazole solubility improvement by inclusion in (2-hydroxy)propyl-beta-cyclodextrin (HPBCD) and simultaneous manipulation of pH of the medium and addition of polyvinylpyrrolidone. Aripiprazole-HPBCD complexes were prepared by spray drying aqueous drug-HPBCD solutions, and their properties were compared with those prepared by solvent-drop co-grinding and physical mixing. The obtained powders were characterized by thermoanalytical methods (TGA and DSC), FTIR spectroscopy, their dissolution properties were assessed, while the binding of aripiprazole into the cavity of HPBCD was studied by molecular docking simulations. The solubilization capacity was found to be dependent on pH as well as the buffer solution's ionic composition. The presence of PVP in the formulation could affect the solubilization capacity significantly, but further experimentation is required before its effect is fully understood. On the basis of solubility studies, the drug/HPBCD stoichiometry was found to be 1:3. The spray-dried products were free of crystalline aripiprazole, they possessed higher solubility and dissolution rate, and were stable enough over a prolonged period of storage. Spray drying of cyclodextrin solutions proved to be an appropriate and efficient technique for the preparation of highly soluble inclusion compounds of aripiprazole and HPBCD

CRYSTALLISATION OF DRUGS IN PRESENCE OF POLYMERS BY THE SOLVENT CHANGE TECHNIQUE AND EFFECTS ON THEIR TABLETTING PROPERTIES

PARACETAMOL WAS CRYSTALLISED FROM ETHANOL-WATER SOLUTIONS IN PRESENCE OF POLYMERS, SUCH AS AGAR, GELATIN, POLYETHYLENGLYCOL 4000 AND POLYVINYLPYROLIDONE 10000. CRYSTAL YIELD, MICROMERITIC AND CRYSTAL PROPERTIES, AS WELL AS COMPRESSION PARAMETERS WERE EVALU ATED. IT WAS FOUND THAT FORMATION (YIELD AND SIZE) OF CRYSTALS INCREASES WITH THE PRESENCE OF AGAR, GELATIN AND PEG, ATTAINS MAXIMUM AND THEN DECREASES, WHILE THE PRESENCE OF PVP INHIBITS CRYSTAL FORMATIONATA ANY CONCENTRATION EXAMINED. THESE EFFECTS ARE ATTRIBUTED TO FLOCCULATION AND FUNCTION OF POLYMERS AS "HETERONUCLEI". REDUCTION OF TRUE DENSITY AND INCREASE OF ΔHF OCCUR IN PRESENCE OF AGAR AND PEG. GELATIN OR PVP CONTRIBUTE TO DECREASED ΔHF AND YIELD PRESSURE AS WELL. SPHERICAL AGGLOMERATION OF IBUPRO FEN WAS ATTEMPTED BY THE SOLVENT CHANGE TECHNIQUE, IN PRESENCE OF FOUR EUDRAGIT POLYMERS (S100, L100, RS AND RL). CRYSTALLISATION PARAMETERS (YIELD, CONDITIONS FOR MASSIVE CRYSTALLISATION, LOADING EFFICIENCY IS INCREASED IN PRESENCE OF THE WATER INSOLUBLE EUDRAGIT RS AND RL, WHICH ARE ATTRIBUTED TO MICELLISATION. SIZE OF SPHERICAL CRYSTAL AGGLOMERATES DECREASES, IN GENERAL, WHILE POROSITY, SPHERICITY AND SURFACE ROUGHNESS INCREASE WITH THE PRESENCE OF POLYMERS AND ALL THESE ALTERATION DEPEND ON THE NATURE OF THE POLYMER AND ARERELATED WITH CHANGES IN HABIT AND GROWTH RATE OF IBUPROFEN MICROCRYSTALS, ASWELL AS TO THEIR COATING BEFORE BINDING INTO SPHERICAL AGGLOMERATES. FLOW ORPACKING AND DENSIFICATION AT LOW COMRESSION ARE DETERMINED BY THE PARTICLE DENS ITY OR INTRAPARTICLE POROSITY, SIZE AND SURFACE ROUΠΑΡΑΚΕΤΑΜΟΛΗ ΚΡΥΣΤΑΛΛΩΘΗΚΕ ΑΠΟ ΥΔΑΤΟ-ΑΙΘΑΝΟΛΙΚΑ ΔΙΑΛΥΜΑΤΑ ΠΑΡΟΥΣΙΑ ΠΟΛΥΜΕΡΩΝ,ΟΠΩΣ: ΑΓΑΡ, ΖΕΛΑΤΙΝΗ, ΠΟΛΥΑΙΘΥΛΕΝΟΓΛΥΚΟΛΗ 4000 ΚΑΙ ΠΟΛΥΒΙΝΥΛΟΠΥΡΟΛΙΔΟΝΗ 10000. ΠΡΟΣΔΙΟΡΙΣΤΗΚΑΝ Η ΑΠΟΔΟΣΗ, ΣΩΜΑΤΙΔΙΑΚΕΣ ΚΑΙ ΚΡΥΣΤΑΛΛΙΚΕΣ ΙΔΙΟΤΗΤΕΣ, ΚΑΘΩΣ ΚΑΙ ΠΑΡΑΜΕΤΡΟΙ ΣΥΜΠΙΕΣΗΣ ΤΩΝ ΚΡΥΣΤΑΛΛΩΝ. ΒΡΕΘΗΚΕ ΟΤΙ Η ΠΑΡΟΥΣΙΑ ΑΓΑΡ, ΖΕΛΑΤΙΝΗΣ ΚΑΙ PEG ΑΥΞΑΝΕΙ ΤΟ ΣΧΗΜΑΤΙΣΜΟ (ΑΠΟΔΟΣΗ ΚΑΙ ΜΕΓΕΘΟΣ) ΤΩΝ ΚΡΥΣΤΑΛΛΩΝ ΜΕΧΡΙΚΑΠΟΙΟ ΟΡΙΟ ΚΑΙ ΣΤΗ ΣΥΝΕΧΕΙΑ ΤΟΝ ΠΕΡΙΟΡΙΖΕΙ, ΕΝΩ ΤΗΣ PVP ΤΟΝ ΠΕΡΙΟΡΙΖΕΙ ΓΕΝΙΚΑ. ΟΙ ΕΠΙΔΡΑΣΕΙΣ ΑΥΤΕΣ ΑΠΟΔΙΔΟΝΤΑΙ ΣΤΗΝ ΚΡΟΚΚΙΔΩΣΗ ΤΩΝ ΠΟΛΥΜΕΡΩΝ, ΚΑΙ ΤΗΝ ΛΕΙΤΟΥΡΓΙΑ ΤΟΥΣ ΩΣ ΠΥΡΗΝΩΝ ΚΡΥΣΤΑΛΛΩΣΕΩΣ. ΜΕΙΩΣΗ ΤΗΣ ΠΥΚΝΟΤΗΤΑΣ ΚΑΙ ΑΥΞΗΣΗ ΤΗΣ ΕΝΘΑΛΠΙΑΣ ΤΗΞΕΩΣ ΠΑΡΑΤΗΡΗΘΗΚΕ ΣΤΙΣ ΠΕΡΙΠΤΩΣΕΙΣ ΑΓΑΡ ΚΑΙ PEG. Η ΖΕΛΑΤΙΝΗ ΚΑΙ Η PVP ΜΕΙΩΝΟΥΝ ΤΗΝ ΕΝΘΑΛΠΙΑ ΤΗΞΕΩΣ ΚΑΙ ΤΗΝ ΠΙΕΣΗ ΥΠΟΧΩΡΗΣΗΣ. ΣΦΑΙΡΙΚΗ ΚΡΥΣΤΑΛΛ ΟΠΟΙΗΣΗ ΙΜΠΟΥΠΡΟΦΑΙΝΗΣ ΕΠΙΧΕΙΡΗΘΗΚΕ ΠΑΡΟΥΣΙΑ ΠΟΛΥΜΕΡΩΝ EUDRAGIT (S100, L100,RS ΚΑΙ RL) ΚΙΑΙ ΠΡΟΣΔΙΟΡΙΣΤΗΚΑΝ ΠΑΡΑΜΕΤΡΟΙ ΤΗΣ ΚΡΥΣΤΑΛΛΩΣΗΣ (ΑΠΟΔΟΣΗ, ΣΥΝΘΗΚΕΣ ΜΑΖΙΚΗΣ ΚΡΥΣΤΑΛΛΩΣΗΣ ΚΑΙ ΜΕΣΟΣ ΡΥΘΜΟΣ ΑΝΑΠΤΥΞΗΣ), ΦΥΣΙΚΟΜΗΧΑΝΙΚΕΣ ΙΔΙΟΤΗΤΕΣ, ΚΑΘΩΣ ΕΠΙΣΗΣ Η ΙΚΑΝΟΤΗΤ Α ΦΟΡΤΙΣΗΣ ΚΑΙ Η IN VITRO ΑΠΟΔΕΣΜΕΥΣΗ. ΒΡΕΘΗΚΕ ΟΤΙΗ ΑΠΟΔΟΣΗ ΠΕΡΙΟΡΙΖΕΤΑΙ ΚΑΙ Η ΙΚΑΝΟΤΗΤΑ ΦΟΡΤΙΣΗΣ ΑΠΟΚΛΙΝΕΙ ΑΠΟ ΤΗΝ ΑΝΑΜΕΝΟΜΕΝΗ ΣΤΗΝ ΠΕΡΙΠΤΩΣΗ ΤΩΝ EUDRAGIT RS ΚΑΙ RL, ΛΟΓΩ ΣΧΗΜΑΤΙΣΜΟΥ ΜΙΚΚΥΛΙΩΝ. ΜΕ ΤΗΝΠΑΡΟΥΣΙΑ ΤΩΝ ΠΟΛΥΜΕΡΩΝ EUDRAGIT, ΓΕΝΙΚΑ, ΤΟ ΜΕΓΕΘΟΣ Τ ΩΝ ΜΙΚΡΟΣΦΑΙΡΙΔΙΩΝ ΜΕΙΩΝΕΤΑΙ ΕΝΩ ΤΟ ΠΟΡΩΔΕΣ, Η ΣΦΑΙΡΙΚΟΤΗΤΑ ΚΑΙ Η ΕΠΙΦΑΝΕΙΑΚΗ ΤΡΑΧΥΤΗΤΑ ΑΥΞΑΝΟΥΝ ΚΑΙ ΟΙ ΜΕΤΑΒΟΛΕΣ ΤΟΥΣ ΕΞΑΡΤΩΝΤΑΙ ΑΠΟ ΤΟ ΕΙΔΟΣ ΤΩΝ ΠΟΛΥΜΕΡΩΝ ΚΑΙ ΑΠΟΔΙΔΟΝΤΑΙ ΣΕΜΕΤΑΒΟΛΕΣ ΤΗΣ ΟΨΗΣ ΚΑΙ ΤΟΥ ΡΥΘΜΟΥ ΑΝΑΠΤΥΞΗΣ ΤΩΝ ΜΙΚΡΟΚΡΥΣΤΑΛΛΩΝ, ΚΑΘΩΣ ΚΑΙ ΤΗΝ ΕΠΙΚΑΛΥΨΗ ΑΥΤΩΝ ΠΡΙΝ ΑΠΟ ΤΗ ΣΥΣΣΩΜΑΤΩΣΗ ΤΟΥΣ. Η ΡΟ

Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs

Cocrystals can be used as an alternative approach based on crystal engineering to enhance specific physicochemical and biopharmaceutical properties of active pharmaceutical ingredients (APIs) when the approaches to salt or polymorph formation do not meet the expected targets. In this article, an overview of pharmaceutical cocrystals will be presented, with an emphasis on the intermolecular interactions in cocrystals and the methods for their preparation. Furthermore, cocrystals of direct pharmaceutical interest, along with their in vitro properties and available in vivo data and characterization techniques are discussed, highlighting the potential of cocrystals as an attractive route for drug development

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

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

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

Influence of hydrophilic polymers on the complexation of carbamazepine with hydroxypropyl-beta-cyclodextrin

In this study binary carbamazepine-hydroxypropyl-beta-cyclodextrin, as well as ternary carbamazepine-hydroxypropyl-beta-cyclodextrin-hydrophilic polymer systems were used to improve dissolution rate of carbamazepine. It has been shown that addition of hydrophilic polymers (Soluplus (R) and two types of hydroxypropyl methylcellulose-Metolose (R) 90SH-100 and Metolose (R) 65SH-1500) significantly increased solubilization capacity of hydroxypropyl-B-cyclodextrin for carbamazepine. Evaluation of carbamaze pine-hydroxypropyl-beta-cyclodextrin-hydrophilic polymer interactions using molecular modeling techniques showed interactions between carbamazepine, which dissociates from inclusion complexes and hydroxypropyl methylcellulose that can prevent crystallization of dissolved carbamazepine. These results can contribute to better understanding of drug-cyclodextrin-hydrophilic polymer interactions which are still not well understood. After evaluation of carbamazepine solubilization with hydroxypropyl-beta-cyclodextrin and hydrophilic polymers, both binary carbamazepine-hydroxypropyl-beta-cyclodextrin and ternary carbamazepine-hydroxypropyl-beta-cyclodextrin-hydrophilic polymer systems were prepared by spray drying. The results of solid state characterization methods showed amorphous nature of carbamazepine in all spray dried systems, which together with the results of molecular modeling techniques indicates inclusion complex formation. Carbamazepine dissolution rate was significantly improved from spray dried formulations compared to pure drug. Binary carbamazepine-hydroxypropyl-beta-cyclodextrin and ternary carbamazepine-hydroxypropyl-beta-cyclodextrin-Soluplus (R) systems exhibited the fastest carbamazepine release, wherein the entire amount of carbamazepine was released during first 5 min

Spray-dried voriconazole-cyclodextrin complexes: Solubility, dissolution rate and chemical stability

The present work investigates the effect of complexation with hydroxypropyl-beta-cyclodextrin (HPBCD) and 2-O-methyl-beta-cyclodextrin (2-O-MBCD), on voriconazole solubility, dissolution rate and chemical stability. Drug-cyclodextrin complexes were prepared as aqueous solutions, which were spray-dried, and their properties were compared to wet ground samples and physical mixtures. DSC analysis revealed absence of crystalline voriconazole from spray-dried complexes. FTIR spectroscopy indicated changes in the H-bonding network of the hydroxyl groups of cyclodextrin following drug inclusion. Dissolution rate of voriconazole was significantly higher from spray-dried complexes with either cyclodextrin in comparison with free drug, physical mixtures, or wet ground mixtures. However, two degradation impurities were found in aged samples, with slightly higher impurity level with HPBCD. Performed solubility studies suggested that 2-O-MBCD is more efficient solubilizer. Molecular docking simulations showed a difference in the 1:1 binding affinities and sites, with HPBCD surprisingly forming complexes of much lower energy, thus suggesting a multiple rather than a 1:1 complexation