Article

Application of Spray Freeze Drying to Theophylline-Oxalic Acid Cocrystal Engineering for Inhaled Dry Powder Technology

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Abstract

Spray freeze drying (SFD) produces suitable particles for the pharmaceutical formulation of dry powders used in dry powder inhalers (DPIs). However, SFD particles have large specific surface area and are partially made up of amorphous solids; this state is hygroscopic and would lead to changes in physicochemical properties by humidity when the particles are stored over the long-term or under high humidity conditions such as in the lungs. This study focused on the application of SFD with a cocrystal technique which can add humidity resistance to the active pharmaceutical ingredients (APIs), and the investigation of the physicochemical properties under high humidity conditions. Cocrystal samples containing theophylline anhydrate (THA) and oxalic acid (OXA) in a molar ratio of 2:1 were prepared by SFD. The crystalline structure, thermal behavior, solid-state, hygroscopicity, stability, and aerodynamic properties were evaluated. Simultaneous in situ measurement by near-infrared and Raman (NIR-Raman) spectroscopy was performed to analyze the humidification process. The SFD sample had a porous particle and an optimal aerodynamic particle size (3.03 μm) although the geometric particle diameter was 7.20 μm. In addition, the sample formed the THAOXA cocrystal with partial coamorphous. The hydration capacity and pseudopolymorphic transformation rate of the SFD sample were much lower than those of THA under conditions of 96.4% relative humidity and 40.0 °C temperature because of the cocrystal formation. The reasons were discussed based on the crystalline structure and energy. The SFD technology for cocrystallization would enable the pharmaceutical preparation of DPI products under environmentally friendly conditions.

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... Different methods have been reported for producing inhalable cocrystal DPIs, namely liquid assisted grinding, 188 milling, 189,190 spray drying, 92,188,191 and spray freeze drying. 192 It is widely recognized that particles with a mass median aerodynamic diameter (MMAD) between 1 and 5 μm are ideal for deep lung delivery. 193 Hence, spray drying and spray freeze drying stand out as the most suitable techniques as one can manipulate the aerosolization attributes (e.g., size, density, and morphology) by customizing different processing parameters in a reproducible, continuous, and scalable manner. ...
... 191 Moreover, a coamorphous theophylline-oxalic acid cocrystal was generated by Tanaka et al. using spray freeze drying with an MMAD of 3.03 μm, which showed an improved hygroscopicity and reduced pseudopolymorphic transformation. 192 In contrast, Alhalaweh et al. demonstrated the possibility of obtaining highly crystalline inhalable theophylline (THP) cocrystals with urea (URE), saccharin (SAC), and nicotinamide (NIC) via spray drying. 189 THP-NIC had a higher fine particle fraction than THP, whereas the formation of THP-URE and THP-SAC cocrystals deteriorated the overall aerosol properties. ...
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Cocrystals are an emerging class of crystalline materials composed of two or more different molecules in the same crystal lattice that are physically connected by non-ionic and non-covalent bonds. Formulating problematic drugs into cocrystals is a pragmatic strategy to manipulate solid state properties for new drug development and product reformulation. While research on cocrystals has been undergoing rapid growth over the past two decades, successful clinical translation of cocrystals is still limited. As the pharmaceutical properties of a cocrystal are decidedly dictated by the selection of cocrystal formers and resulting crystal structure, the present review begins with an overview of the current strategies in cocrystal design and preparation, followed by the potential applications of cocrystals in medicines. The major hurdles and missing knowledge gaps hindering the translation of pharmaceutical cocrystals into commercial reality are also mentioned. Finally, perspectives of cocrystals in alternative dosage forms other than for oral use, as well as latest topics of cocrystal research are highlighted. We believe that cocrystals play an important role in future drug discovery and development, offering a new direction for optimal drug delivery, combination therapy and personalized medicines.
... Although the exact mechanism involved in the spray drying process is unknown, it is assumed that the first nucleation starts in supersaturated solution and then crystal growth takes place due to solvent evaporation [45]. Tanaka et al. prepared theophylline-oxalic acid cocrystal by spray freeze drying technology for pulmonary application [65]. Weng et al. reported spray dried itraconazole-suberic acid cocrystal with superior micromeritics properties for pulmonary drug delivery [66]. ...
... Other examples includes theophylline-oxalic acid cocrystals prepared by spray freeze drying process for dry powder inhalers (DPIs). Theophylline -oxalic acid cocrystal exhibited improved hygroscopicity, good aerodynamics, and reduced pseudopolymorphic transformation to be used as DPIs [65]. ...
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... Voriconazole powder prepared by spray-freeze-drying exhibited porous and spherical structure, and displayed crystalline characteristics (Liao et al., 2019). However, the spray-freezedrying particles are partially composed of amorphous solids with a large specific surface area, and this state is hygroscopic which can lead to changes in physicochemical properties by humidity when the particles are stored over the longterm or under high humidity conditions such as in the lungs (Tanaka et al., 2020). Cocrystal technique has been used to solve such problems (Duggirala et al., 2016;Al-Obaidi et al., 2021). ...
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Pulmonary inhalation administration is an ideal approach to locally treat lung disease and to achieve systemic administration for other diseases. However, the complex nature of the structural characteristics of the lungs often results in the difficulty in the development of lung inhalation preparations. Nanocrystals technology provides a potential formulation strategy for the pulmonary delivery of poorly soluble drugs, owing to the decreased particle size of drug, which is a potential approach to overcome the physiological barrier existing in the lungs and significantly increased bioavailability of drugs. The pulmonary inhalation administration has attracted considerable attentions in recent years. This review discusses the barriers for pulmonary drug delivery and the recent advance of the nanocrystals in pulmonary inhalation delivery. The presence of nanocrystals opens up new prospects for the development of novel pulmonary delivery system. The particle size control, physical instability, potential cytotoxicity, and clearance mechanism of inhaled nanocrystals based formulations are the major considerations in formulation development. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
... There is still interest in this compound in general and the corresponding solid state phases [10,11] as well as in the corresponding co-crystals [12][13][14][15]. Nowadays theophylline is sometimes used as pharmaceutical agent due to its effects on the respiratory system [16][17][18][19]. Interestingly, theophylline was also tried in COVID-19 therapy [20]. ...
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C21H33Cl9Fe2N12O9, trigonal, R 3 ‾ (no. 148), a = 13.1897(3) Å, c = 39.5222(9) Å, Z = 6, V = 5954.4(3) Å3, R gt (F) = 0.0255, wR ref (F 2) = 0.0743, T = 120 K.
... This highlights the unpredictable nature of coformer selection in cocrystal formation and the importance of considering all aspects of physical property changes. Tanaka et al. produced a theophylline:oxalic acid cocrystal through a combination of spray and freeze drying [174]. When compared to the control, the resulting formulation showed resistance to hygroscopicity and polymorphic transition whilst maintaining good pulmonary delivery. ...
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... There is still a fundamental interest in this compound and the corresponding solid state phases [10,11] and co-crystals [12][13][14][15]. Nowadays theophylline is often used as pharmaceutical agent due to its effects on the respiratory system [16][17][18][19]. Recently, theophylline was also used in SARS-CoV-2 therapy [20]. ...
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... The developed particles were spherical, highly porous, and shown excellent aerosolization efficiency (MMAD 3.20 mm; GSD 1.26) at the core to wall ratio (1:25). In another research, Tanaka et al. [97] addressed the issue of stability of SFD formulation in humid conditions. In this work, they have developed theophylline-oxalic acid cocrystals using SFD technique. ...
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Micronized cocrystal powders and amorphous spray-dried formulations were prepared and evaluated in vivo and in vitro as pulmonary absorption enhancement formulations of poorly soluble itraconazole (ITZ). ITZ cocrystals with succinic acid (SA) or l-tartaric acid (TA) with a particle size diameter of < 2 µm were successfully micronized using the jet-milling system. The cocrystal crystalline morphologies observed using scanning electron microscopy (SEM) suggested particle shapes that differed from those of the crystalline or spray-dried amorphous ITZ. The micronized ITZ cocrystal powders showed better intrinsic dissolution rate (IDR) and pulmonary absorption profile in rats than that of the amorphous spray-dried formulation and crystalline ITZ with comparable particle sizes. Specifically, in rat pharmacokinetic studies following pulmonary administration, micronized ITZ-SA and ITZ-TA cocrystals showed area under the curve from 0-8 h (AUC0-8h) values approximately 24- and 19-fold higher than those of the crystalline ITZ and 2.0- and 1.6-fold higher than the spray-dried ITZ amorphous values, respectively. The amorphous formulation appeared physically instable during the studies due to rapid crystallization of ITZ, which was its disadvantage compared to the crystalline formulations. Therefore, this study demonstrated that micronized cocrystals are promising formulations for enhancing the pulmonary absorption of poorly soluble compounds.
Article
Cocrystals, a long known but understudied class of crystalline solids, have attracted interest from crystal engineers and pharmaceutical scientists in the past decade and are now an integral part of the preformulation stage of drug development. This is largely because cocrystals that contain a drug molecule, pharmaceutical cocrystals, can modify physicochemical properties without the need for covalent modification of the drug molecule. This review presents a brief history of cocrystals before addressing recent advances in design, discovery and development of pharmaceutical cocrystals that have occurred since an earlier review published in 2004. We address four aspects of cocrystals: nomenclature; design using hydrogen-bonded supramolecular synthons; methods of discovery and synthesis; development of pharmaceutical cocrystals as drug products. Cocrystals can be classified into molecular cocrystals (MCCs) that contain only neutral components (coformers) and ionic cocrystals (ICCs), which are comprised of at least one ionic coformer that is a salt. That cocrystals, especially ICCs, offer much greater diversity in terms of composition and properties than single component crystal forms and are amenable to design makes them of continuing interest. Seven recent case studies that illustrate how pharmaceutical cocrystals can improve physicochemical properties and clinical performance of drug substances, including a recently approved drug product based upon an ICC, are presented.
Article
Anhydrous theophylline exhibited polymorphism and two modifications, which were named form I and form II, were isolated. The melting point and the enthalpy of fusion of each polymorph determined by differential scanning calorimetry (DSC) were 273.4±1.0°C and 26.4±0.3 kJ/mol for form I and 269.1±0.4°C and 28.2±1.1 kJ/mol for form II. The higher melting form I had a smaller density. In contrast to caffeine, theophylline formed a monohydrate. The dissociation vapor pressure curves of theophylline hydrate and caffeine hydrate were obtained and the difference in their stabilities was discussed. The enthalpy of dehydration was determined by DSC under closed conditions. The dehydration under isothermal conditions appeared to proceed acoording to the mechanism of random uncleation followed by two-dimensional growth of nuclei as represented by the Avrami-Erofe'ev equation. The solubilities of theophylline and its hydrate were determined as a function of temperature. From the van't Hoff type plot, the transition temperature between the hydrate and the anhydrous form was determined.
Article
The effects of specific drug-polymer interactions (ionic or hydrogen-bonding) on the molecular mobility of model amorphous solid dispersions (ASDs) were investigated. ASDs of ketoconazole (KTZ), a weakly basic drug, with each of polyacrylic acid (PAA), poly(2-hydroxyethyl methacrylate) (PHEMA) and polyvinylpyrrolidone (PVP) were prepared. Drug-polymer interactions in the ASDs were evaluated by IR and solid-state NMR, the molecular mobility quantified by dielectric spectroscopy and crystallization onset monitored by differential scanning calorimetry (DSC) and variable temperature X-ray diffractometry (XRD). KTZ likely exhibited ionic interactions with PAA, hydrogen-bonding with PHEMA and weaker dipole-dipole interactions with PVP. Based on dielectric spectroscopy, the α-relaxation times of the ASDs followed the order: PAA > PHEMA > PVP. In addition, the presence of ionic interactions also translated to a dramatic and disproportionate decrease in mobility as a function of polymer concentration. Based on both DSC and variable temperature XRD, an increase in strength of interaction translated to higher crystallization onset temperature and a decrease in extent of crystallization. Stronger drug-polymer interactions, by reducing the molecular mobility, can potentially delay the crystallization onset temperature as well as crystallization extent.
Article
It has been 20 years since the concept of supramolecular synthon was introduced with the purpose of rational supramolecular synthesis. While this concept has been greatly successful in employing a retrosynthetic approach in crystal engineering, the past few years have seen a continuous evolution of supramolecular synthons from being a synthetic subunit to a basic unit for understanding the dynamics of crystallization. This review attempts to give a glimpse of such developments.
Article
Pharmaceutical spray-freeze drying (SFD) includes a heterogeneous set of technologies with primary applications in apparent solubility enhancement, pulmonary drug delivery, intradermal ballistic administration and delivery of vaccines to the nasal mucosa. The methods comprise of three steps: droplet generation, freezing and sublimation drying, which can be matched to the requirements given by the dosage form and route of administration. The objectives, various methods and physicochemical and pharmacological outcomes have been reviewed with a scope including related fields of science and technology. Copyright © 2015. Published by Elsevier B.V.
Article
The solid phases in the theophylline–oxalic acid co-crystal system have been investigated by thermal analysis techniques, X-ray diffraction analysis (XRD) and solubility measurements. The work includes the 2:1 co-crystal of theophylline and oxalic acid, polymorphs of theophylline, the theophylline monohydrate and solid oxalic acid. The DSC curve of the co-crystal presents two endothermic peaks, one at about 230 °C where the oxalic acid in the co-crystal decomposes and carbon dioxide is liberated, and another one at 279 °C where the remaining theophylline melts. At equilibrium with the solid co-crystal, the theophylline concentration is only 60% of the corresponding value for the pure solid theophylline. Using the solubility data, the standard Gibbs free energy of formation of the co-crystal from the pure solid phases is estimated to be approximately −6.0 kJ mole−1. In a chloroform/methanol mixture (4:1 v:v) the commercial form of pure theophylline (Form II) has been observed to transform into a more stable non-solvated form (Form I). The data suggest that the polymorphs are enantiotropically related with an approximate transition temperature of 70 °C. The 2:1 theophylline–oxalic acid co-crystal can be successfully produced by cooling crystallisation in chloroform/methanol mixture (4:1 v:v) and by slurry conversion crystallisation also in more benign solvents.
Article
The first object was to develop an X-ray diffractometric method for the detection and quantification of crystalline sucrose when it occurs as a mixture with amorphous sucrose. Standards consisting of amorphous sucrose physically mixed with 1 to 5 weight percent crystalline sucrose were prepared. The sum of the background subtracted integrated intensities of the 12.7°2θ (6.94 Å) and 13.1°2θ (6.73 Å) sucrose diffraction peaks were linearly related to the weight percent crystalline sucrose. The limits of detection and quantitation of crystalline sucrose were 0.9% and 1.8% w/w, respectively. The second object was to study the kinetics of crystallization of sucrose as a function of temperature (at 102, 105 and 110 °C under a water vapor pressure of 0 Torr) and water vapor pressure (17.4, 19.8 and 21.4 Torr at 27 °C). In all cases, the crystallization kinetics was best described by the Avrami-Erofe’ev model (three-dimensional nucleation).
Article
In this study, water penetration and the interaction between water and a pharmaceutical excipient in a tablet were investigated using near-infrared (NIR) spectroscopy and perturbation-correlation moving-window two-dimensional correlation spectroscopy (PCMW-2DCS). The penetration rate of water into a tablet was mainly dependent on the porosity of the tablet and was less dependent on the type of excipient. This behavior was well described by the Lucas–Washburn theory. The PCMW-2DCS technique revealed that there are two-staged interaction changes in NIR spectra of the water–powder interactions. The first and second changes corresponded to the water–solid interaction and the dissolution of the solid, respectively. The diffusion-controlled dissolution model by Nernst well explained these results.
Article
Theophylline and methyl gallate can form a 1:1 co-crystal. Their tableting performance follows the order of theophylline > co-crystal ≫ methyl gallate. While co-crystallization profoundly improves the tabletability of methyl gallate, it significantly deteriorates that of theophylline. This difference in bulk compaction behaviour originates from the dissimilar crystal plasticity and elasticity, which results from unique molecular packing features in the respective crystal lattices. The presence of a three-dimensional hydrogen bonded network gives rise to very low plasticity in the methyl gallate crystal, which leads to its poor tabletability. In contrast, the layers of two-dimensional rigid, hydrogen bonded molecules in the co-crystal improve the crystal plasticity, by facilitating slip with shear that, in turn, enhances tabletability. However, theophylline undergoes plastic deformation more readily when compared to the co-crystal, because the slip layers in theophylline are composed of hydrogen bonded columns, which provide additional flexibility for slip. As a consequence, theophylline crystals have significantly enhanced tabletability.
Article
The crystal structure of the title compound, 3,7-di­hydro-1,3-di­methyl-1H-purine-2,6-dione monohydrate, C7H8N4O2·H2O, was determined by single-crystal X-ray diffractometry using direct methods. Water mol­ecules in the crystals form infinite chains, through hydrogen-bonded chains running through tunnels formed by surrounding theophyl­line mol­ecules along the a axis. The water chains are also crosslinked through hydrogen bonds by hydrogen-bonded theophyl­line dimers, and form a two-dimensional hydrogen-bonded structure parallel to the ab plane. The previously reported structure [Suctor (1958), Acta Cryst. 11, 83–87] in space group P21, with Z = 4, appears to be incorrect.
Article
Questions relating to the prediction of the crystal structure or structures of a given organic molecule may be more gainfully reversed so that retrosynthetic analysis of a target crystal network leads to the identification of molecular precursors. Crystal engineering is solid state supramolecular synthesis and supramolecular synthons, units formed by synthetic operations involving intermolecular interactions, may be used to focus efforts in such logic-driven retrosynthesis.
Article
Transport and fate of inhaled particulate matter in the human lungs is calculated for realistic physicochemical conditions by a new dosimetry model. The model solves a variant of the general dynamic equation for the size evolution of respirable particles within the human tracheobronchial airways, starting at the tracheal entrance. We focus on ambient anthropogenic aerosols, which are of concern in inhalation toxicology because of their potential irritant and toxic effects on humans. The aerosols considered are polydisperse with respect to size and heterodisperse with respect to thermodynamic state and chemical composition, having initially bimodal lognormal size distribution that evolves with time as a result of condensation-evaporation and deposition processes. The architecture of the human lung is described by Weibel's symmetric bronchial tree. Simulations reveal that, due to the rapid growth of submicron-sized particles, increased number and mass fractions of the particle population can be found in the intermediate size range 0.1 < φ < 1
Article
A brief and systematic overview of recent advances in understanding the mechanism of mechanochemical cocrystallization at macroscopic (bulk phase transformations) and microscopic levels (molecular recognition) is given. The review particularly addresses neat and liquid-assisted grinding approaches to cocrystal formation.
Article
Spray drying is a well established technique for material processing and scale-up. This study investigated the formation of pharmaceutical cocrystals by spray drying. The cocrystal formation mechanisms in spray-drying and solution methods, based on triangular phase diagrams, are discussed. The solvent evaporation of stoichiometric solutions of incongruently saturating cocrystals resulted in a mixture of phases, as dictated by the thermodynamic phase diagram. In contrast, spray drying of similar solutions of incongruently saturating systems generated pure cocrystals. It is thus suggested that the formation of cocrystals by spray drying could be kinetically controlled and/or mediated by the glassy state of the material.
Article
To explore in-situ forming cocrystal as a single-step, efficient method to significantly depress the processing temperature and thus minimize the thermal degradation of heat-sensitive drug in preparation of solid dispersions by melting method (MM) and hot melt extrusion (HME). Carbamazepine (CBZ)-nicotinamide (NIC) cocrystal solid dispersions were prepared with polymer carriers PVP/VA, SOLUPLUS and HPMC by MM and/or HME. The formation of cocrystal was investigated by differential scanning calorimetry and hot stage polarized optical microscopy. State of CBZ in solid dispersion was characterized by X-ray powder diffraction and optical microscopy. Interactions between CBZ, NIC and polymers were investigated by FTIR. Dissolution behaviors of solid dispersions were compared with that of pure CBZ. CBZ-NIC cocrystal with melting point of 160°C was formed in polymer carriers during heating process, and the preparation temperature of amorphous CBZ solid dispersion was therefore depressed to 160°C. The dissolution rate of CBZ-NIC cocrystal solid dispersion was significantly increased. By in-situ forming cocrystal, chemically stable amorphous solid dispersions were prepared by MM and HME at a depressed processing temperature. This method provides an attractive opportunity for HME of heat-sensitive drugs.
Article
Spray-freeze drying (SFD) is an attractive technique to prepare highly porous dry powders for inhalation. However, there have been few reports of its application to dry powder inhalers (DPIs). Therefore, in this study, we prepared dry plasmid DNA (pDNA) powders with different molecular ratios of chitosan to pDNA (N/P ratios) by SFD. All the pDNA powders were spherical and highly porous, with particles approximately 20-40microm in geometric diameter. The morphology changed little with the alteration of the N/P ratio. On electrophoresis, a band of linear pDNA was detected in the preparation without chitosan, suggesting the destabilization of pDNA through SFD. However, the addition of chitosan protected pDNA from destabilization. Moreover, the pDNA powders were evaluated for pulmonary gene transfection efficiency using an in vivo dual imaging technique for gene DPIs developed previously. Maximum gene expression was observed at 9-12h following pulmonary administration of the powders into mice. The powder with the N/P ratio of 10 had the highest gene transfection efficiency. A higher affinity of chitosan for pDNA and a smaller (approximately 100nm) pDNA/chitosan complex (N/Pf10) were found at pH 6.5 (in lung) than at pH 7.4 (in physiological conditions), suggesting that the effective compaction of pDNA by chitosan at the N/P ratio of 10 at pH 6.5 contributes to the gene transfection efficiency in the lung. These results suggest inhalable dry pDNA powders with chitosan prepared by SFD to be a suitable formulation for pulmonary gene therapy.
Article
Insulin loaded PLGA nanospheres having weight mean diameters of 400 nm were prepared by the modified emulsion solvent diffusion method in water. The nanosphere recovery and the drug recovery in the nanospheres were 74.8%+/-4.71 and 46.8%+/-7.01, respectively. Eighty five percent of the drug was released from the nanospheres at the initial burst, followed by prolonged releasing of the remaining drug for a few hours in saline at 37 degrees C. The aqueous dispersions (6 mg/ml) of PLGA nanospheres were nebulized by a sieve type ultrasonic nebulizer to discrete droplets of 5 approximately 7 microm in mean diameters, 75% of which were successfully delivered into the alveolar fraction in a cascade impactor inhaled at 28.3 l/min. The nebulized PLGA nanospheres were administered via a spacer by using a constant volume respirator into the trachea of the fasted guinea pig for 20 min. After the administration of 3.9 I.U./kg insulin with the PLGA nanospheres, the blood glucose level was reduced significantly and the hypoglycemia was prolonged over 48 h, compared to the nebulized aqueous solution of insulin as a reference (6 h). This result could be attributed to the sustained releasing of insulin from the nanospheres deposited widely on to the whole of lung.
Article
The crystal structure of the equimolar trimethoprim (TMP) and sulfamethoxypyridazine (SMPD) complex in the anhydrous form (TMP. SMPD) and that of the species with 1.5 molecules of water of crystallization (TMP.SMPD.W) are reported in this article. X-ray powder diffraction patterns (both computer generated and experimental) and thermal analytical data from differential scanning calorimetry (DSC) and thermogravimetry useful for the characterization of TMP.SMPD and TMP.SMPD.W are provided. The stability of TMP.SMPD.W, which retains its crystallographic order under 0% relative humidity (RH) conditions at room temperature (22 degrees C) and 20 mmHg, is accounted for in terms of crystal structure and hydrogen bonding. Transformation of TMP.SMPD to the hydrate complex by exposure to approximately 100% RH, suspension in water, and wet granulation, and dehydration of TMP.SMPD.W by thermal treatment and by desiccation with methanol were investigated and tentatively interpreted in terms of crystal properties. Interactions in the physical mixture of TMP and SMPD by grinding, compression, heating, and contact with water were also studied. Water-mediated formation of TMP.SMPD.W by wetting and metastable eutectic melting-mediated formation of TMP.SMPD by heating was demonstrated. Mechanical activation by milling makes the physical mixture prone to solid-state transformation into dimorphic anhydrous cocrystals by supply of thermal energy during a DSC scan.
Article
The search for alternatives to metered-dose inhalers has accelerated recently in a bid to find effective products that do not use chlorofluorocarbon (CFC) propellants. This paper reviews the factors to be considered in developing dry powder inhalers (DPIs), particularly the formulation, metering design and flow path in the device. The advantages and disadvantages of current DPIs are discussed and possible future approaches outlined.
Article
The purpose of this investigation was i) to study the effect of physical aging on crystallization and water vapor sorption behavior of amorphous anhydrous trehalose prepared by freeze-drying, and ii) to determine the effects of water sorption on the relaxation state of the aged material. Freeze-dried trehalose was aged at 100 dgrees C for varying time periods to obtain samples with different degrees of relaxation. The glass transition temperature (Tg) and enthalpic relaxation were determined by differential scanning calorimetry, and the rate and extent of water uptake at different relative humidity values were quantified using an automated vapor sorption balance. Annealing below the Tg caused nucleation in the amorphous trehalose samples, which decreased the crystallization onset temperature on subsequent heating. However, no crystallization was observed below the Tg even after prolonged annealing. Physical aging caused a decrease in the rate and extent of water vapor sorption at low relative humidity values. Moreover, the water sorption removed the effects of physical aging, thus effectively causing enthalpic recovery in the aged samples. This recovery occurred gradually in the glassy phase and was not associated with a glass to rubber transition. We believe this aging reversal to be due to volume expansion during water sorption in the amorphous structure. Thermal history of amorphous materials is a crucial determinant of their physical properties. Aging of amorphous trehalose led to nucleation below the Tg, and decrease in rate and extent of water sorption. Sorption of water resulted in irreversible changes in the relaxation state of the aged material.
Article
Pulmonary drug delivery is increasingly appreciated as a route of administration for systemically acting proteins and peptides. A respirable particle size of the drug is a key requirement, but the fragile nature of many proteins may be a limitation for the application of conventional production processes. The aim of this study was to examine the effect of different micronisation processes on the degradation and aerodynamic properties of the GnRH-antagonist cetrorelix in order to enable its application by a dry powder inhaler (Novolizer). A modified pearl mill was used for milling in fluid propellant. Furthermore, a spray drying procedure was established using a novel process of atomisation and drying. Adhesive mixtures of lactose and 5-20% of micronised cetrorelix-acetate were prepared. Analysis by laser light scattering, HPLC, Karl Fischer, cascade impactor and scanning electron microscopy were performed to characterise the manufactured powders. Both micronisation procedures succeeded in producing small range particle size distributions, suitable for deep lung deposition (D50 = 1.6 microm for milling and 3.3 microm for spray drying). The pearl milled cetrorelix showed promising results when delivered by the Novolizer: a reproducible and highly efficient dispersion of the drug was achieved (around 60% of aerosolised drug < 5 microm). The spray dried drug was not suitable when processed as adhesive mixture.
Article
The crystal form adopted by the respiratory drug theophylline was modified using a crystal engineering strategy in order to search for a solid material with improved physical stability. Cocrystals, also referred to as crystalline molecular complexes, were prepared with theophylline and one of several dicarboxylic acids. Four cocrystals of theophylline are reported, one each with oxalic, malonic, maleic and glutaric acids. Crystal structures were obtained for each cocrystal material, allowing an examination of the hydrogen bonding and crystal packing features. The cocrystal design scheme was partly based upon a series of recently reported cocrystals of the molecular analogue, caffeine, and comparisons in packing features are drawn between the two cocrystal series. The theophylline cocrystals were subjected to relative humidity challenges in order to assess their stability in relation to crystalline theophylline anhydrate and the equivalent caffeine cocrystals. None of the cocrystals in this study converted into a hydrated cocrystal upon storage at high relative humidity. Furthermore, the theophylline:oxalic acid cocrystal demonstrated superior humidity stability to theophylline anhydrate under the conditions examined, while the other cocrystals appeared to offer comparable stability to that of theophylline anhydrate. The results demonstrate the feasibility of pharmaceutical cocrystal design based upon the crystallization preferences of a molecular analogue, and furthermore show that avoidance of hydrate formation and improvement in physical stability is possible via pharmaceutical cocrystallization.
Article
Theophylline is known to undergo vapor phase induced hydrate-anhydrate pseudopolymorphic transformations, which can affect its bioavailability. In this work, the kinetics of the pseudopolymorphic transitions of theophylline crystals in different storage conditions is studied using a vibrational spectroscopic technique. While the hydration is a single-step process with a half-life time of ca. 5 h, the dehydration occurs through a two-step mechanism. In addition, the phase stability of hydrate-anhydrate systems in different relative humidity (RH) conditions was probed. The critical RH for anhydrous teophylline was found to be at ca. 79%, while the critical RH for dehydration is ca. 30%.
Article
The increasing prevalence of poorly soluble drugs in development provides notable risk of new products demonstrating low and erratic bioavailability with consequences for safety and efficacy, particularly for drugs delivered by the oral route of administration. Although numerous strategies exist for enhancing the bioavailability of drugs with low aqueous solubility, the success of these approaches is not yet able to be guaranteed and is greatly dependent on the physical and chemical nature of the molecules being developed. Crystal engineering offers a number of routes to improved solubility and dissolution rate, which can be adopted through an in-depth knowledge of crystallisation processes and the molecular properties of active pharmaceutical ingredients. This article covers the concept and theory of crystal engineering and discusses the potential benefits, disadvantages and methods of preparation of co-crystals, metastable polymorphs, high-energy amorphous forms and ultrafine particles. Also considered within this review is the influence of crystallisation conditions on crystal habit and particle morphology with potential implications for dissolution and oral absorption.
Article
To design and prepare cocrystals of indomethacin using crystal engineering approaches, with the ultimate objective of improving the physical properties of indomethacin, especially solubility and dissolution rate. Various cocrystal formers, including saccharin, were used in endeavours to obtain indomethacin cocrystals by slow evaporation from a series of solvents. The melting point of crystalline phases was determined. The potential cocrystalline phase was characterized by DSC, IR, Raman and PXRD techniques. The indomethacin-saccharin cocrystal (hereafter IND-SAC cocrystal) structure was determined from single crystal X-ray diffraction data. Pharmaceutically relevant properties such as the dissolution rate and dynamic vapour sorption (DVS) of the IND-SAC cocrystal were evaluated. Solid state and liquid-assisted (solvent-drop) cogrinding methods were also applied to indomethacin and saccharin. The IND-SAC cocrystals were obtained from ethyl acetate. Physical characterization showed that the IND-SAC cocrystal is unique vis-à-vis thermal, spectroscopic and X-ray diffraction properties. The cocrystals were obtained in a 1:1 ratio with a carboxylic acid and imide dimer synthons. The dissolution rate of IND-SAC cocrystal system was considerably faster than that of the stable indomethacin gamma-form. DVS studies indicated that the cocrystals gained less than 0.05% in weight at 98%RH. IND-SAC cocrystal was also obtained by solid state and liquid-assisted cogrinding methods. The IND-SAC cocrystal was formed with a unique and interesting carboxylic acid and imide dimer synthons interconnected by weak N-Hcdots, three dots, centeredO hydrogen bonds. The cocrystals were non-hygroscopic and were associated with a significantly faster dissolution rate than indomethacin (gamma-form).
Article
Atomic force microscopy (AFM) was used to evaluate the particle adhesion and surface morphology of engineered particles for dry powder inhaler (DPI) respiratory therapy to gain a greater understanding of interparticle forces and the aerosolisation process. A series of spherical model drug particles of bovine serum albumin (BSA) was prepared with different degrees of surface corrugation. The particles were evaluated in terms of particle size (laser diffraction) and microscopic morphology (scanning electron microscopy). Conventional tapping mode AFM was used to evaluate the nanoscopic morphology and derive specific roughness parameters, while AFM colloid probe microscopy was used to directly measure the interaction of functionalised probes. The physical characterisation and AFM measurements were evaluated in terms of in vitro aerosolisation performance, using a conventional Rotahaler((R)) DPI and multistage liquid impinger. A direct relationship between the root mean square roughness, particle adhesion and in vitro aerosol performance (measured as fine particle fraction, FPF) was observed suggesting that as the degree of corrugation increased, particle adhesion was reduced which, resulted in a concomitant increase in FPF. This study demonstrates that AFM may be used to predict the aerosolisation performance micron sized particles for inhalation based on their morphological properties.
Pharmaceutical Inhalation Aerosol Technology
  • A J Hickey
  • S R Da Rocha
Safety Data Sheet of Oxalic Acid
  • Ecolab
Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry
  • Drug Food
  • Administration