Stable Anhydrous Form Research Articles

Solid-State Phase Transformation of Monohydrate and Anhydrous Form II of Sitagliptin Phosphate into a Novel Anhydrous Form IV – Solvent-Driven, Temperature-Induced and Stress Testings

The solid form landscape of sitagliptin phosphate was systematically evaluated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy and X-ray powder diffraction (XRPD), supported by a plethora of auxiliary analytical techniques. The preformulation experiments resulted in the transition of sitagliptin phosphate monohydrate into a new anhydrous form (designated as form IV), obtained after recrystallization from absolute ethanol. The anhydrous form IV remained stable under stressed conditions (1 month at 25 °C/60 %RH and 40 °C/75 %RH). On the other hand, thermal heating (dehydration) of sitagliptin phosphate monohydrate resulted in conversion into another anhydrous form II. Form II was found to be metastable, because after melting, under exposure at 40 °C/75 %RH for 1 month, or when dissolved in absolute ethanol converted to the stable anhydrous form IV of sitagliptin phosphate. A monotropic relationship was found between both studied anhydrous forms. Intrinsic dissolution tests revealed differences in the dissolution rates between the monohydrate and the anhydrous forms of sitagliptin phosphate. This research corrects the record with an accurate chemical composition of the anhydrous form IV of sitagliptin phosphate that was previously regarded as a hemiethanolate. In addition, the crystal structure of anhydrous form II of sitagliptin phosphate has been solved and reported for the first time.

Imaging of dehydration in particulate matter using Raman line-focus microscopy

Crystalline solids can incorporate water molecules into their crystal lattice causing a dramatic impact on their properties. This explains the increasing interest in understanding the dehydration pathways of these solids. However, the classical thermal analytical techniques cannot spatially resolve the dehydration pathway of organic hydrates at the single particle level. We have developed a new method for imaging the dehydration of organic hydrates using Raman line-focus microscopy during heating of a particle. Based on this approach, we propose a new metastable intermediate of theophylline monohydrate during the three-step dehydration process of this system and further, we visualize the complex nature of the three-step dehydration pathway of nitrofurantoin monohydrate to its stable anhydrous form. A Raman line-focus mapping option was applied for fast simultaneous mapping of differently sized and shaped particles of nitrofurantoin monohydrate, revealing the appearance of multiple solid-state forms and the non-uniformity of this particle system during the complex dehydration process. This method provides an in-depth understanding of phase transformations and can be used to explain practical industrial challenges related to variations in the quality of particulate materials.

Relative stability of hydrated/anhydrous products of calcium chloride during complete dehydration as examined by high-temperature X-ray powder diffraction

The correlation between the relative stability of hydrated/anhydrous products and microstructure of calcium chloride has been investigated by high-temperature X-ray powder diffraction. The X-ray diffractograms were recorded at 25, 115, 150 and 200 °C, respectively. Results indicate that tetrahydrate and dihydrate are the major forms available at 25 °C. The first endothermic dehydration at around 115 °C is accounted for a mixture of anhydrous calcium chloride and monohydrate. The second consecutive endothermic dehydration at around 150 °C ensured complete removal of crystalline water. The complete dehydration is accounted for two different anhydrous calcium chloride phases with larger (0.324 nm3) and smaller (0.168 nm3) unit cell volume. The phase with smaller unit cell volume is the stable anhydrous form of calcium chloride beyond 150 °C. The relative stability of anhydrous/hydrated products at different temperatures simultaneously determines by respective lattice strain, crystallite size, and unit cell volume. It is also found that inferior lattice strain, larger crystallite size, and smaller unit cell volume ultimately account for dominant and more stable calcium chloride product. The moisture absorption from the material takes place towards reducing lattice strain; hence, the hygroscopic nature of calcium chloride can be somewhat related to microstructure stability at low temperatures.

Iso-Structurality Induced Solid Phase Transformations: A Case Study with Lenalidomide

Lenalidomide (LDM) is a thalidomide analogue known for its immunomodulation, antiangiogenic, and antineoplastic properties. However, to date, only two forms of lenalidomide [Form-1 (anhydrous) and Form-2 (hemihydrate)] are reported in the literature. Through a comprehensive polymorph screening herein, we report five forms of lenalidomide [Form-3 (DMF-solvate), Form-4 (anhydrous), Form-5 (DMSO solvate), Form-6 (acetone solvate), and Form-7 (dihydrate)]. Single crystal structures (for all forms) are established to provide potential knowledge about the intermolecular interactions, three-dimensional structures, and the nature of solvent/water within the lattice. Thermodynamic stability investigations revealed unusual solid state phase transformations which are relatively unexplored to date. It is noteworthy that all solvates upon desolvation convert to Form-1 (thermodynamically stable anhydrous form), whereas all hydrates upon dehydration convert to a metastable Form-4 (novel anhydrous form) which, upon furth...

Control of Crystal Modification and Crystal Shape by Control of Solid–Solid Transitions during Crystallization and Drying: Two Industrial Case Studies

Crystallization and drying are the final steps in the manufacture of most drug substances that determine their final features and may also impact the manufacture of the formulated drug product. It is important to understand and control the mechanisms involved in the crystallization and drying processes to avoid handling and formulation problems, and this is illustrated with two examples of large-scale processes. In the first, a solid–solid phase transition between two very similar crystalline forms was shown to lead to dramatic particle size reduction and consequent processing issues; the unwanted phase transition was avoided by careful choice of crystallization conditions. In the second, control of the drying conditions allowed a rapid solid–solid phase transition of a mixed solvate into a stable anhydrous form.

Two polymorphs and one hydrate of a molecular salt involving phenazopyridine and salicylic acid

Two anhydrous polymorphs (AH-I, AH-II) and one monohydrate (MH) of a molecular salt involving phenazopyridine and salicylic acid, are reported. The charge-assisted N–H⋯O hydrogen bond provides the main driving force for the direct binding of the two compounds. AH-I is the stable anhydrous form with a low hygroscopicity, a high solubility and a simple preparation method.

Thermodynamic Stability Considerations for Isostructural Dehydrates

Nonstoichiometric channel hydrates are a class of crystalline hydrates that can incorporate a range of water levels as a function of temperature and relative humidity (RH). When a nonstoichiometric channel hydrate can dehydrate to yield a physically stable isostructural crystalline lattice, it may become challenging to accurately evaluate the thermodynamic stability relationship associated with a polymorphic system using traditional methods. This work demonstrates application of a eutectic-melting method to determine the stability relationship between a nonstoichiometric channel dehydrate and an anhydrous form. A transition temperature (122°C) between the isostructural dehydrate of the nonstoichiometric channel hydrate and the anhydrous polymorph was identified, with the nonstoichiometric channel hydrate being the thermodynamically stable anhydrous form at room temperature (RT). Solid-state storage at a range of RH conditions demonstrated that the nonstoichiometric channel hydrate is also the stable form at RT above an RH of 94%. These results demonstrate that the nonstoichiometric channel hydrate is the stable form at low temperatures, independent of its hydration state. It has been demonstrated that the eutectic-melting method is applicable to the study of thermodynamic stability relationships between anhydrous forms and dehydrated channel hydrates.

Formation of a new crystalline form of anhydrous β-maltose by ethanol-mediated crystal transformation

β-Maltose monohydrate was transformed into an anhydrous form by ethanol-mediated method under several temperatures with agitation. A new stable anhydrous form of β-maltose (Mβs) was obtained, as substantiated by the X-ray diffraction patterns. Mβs obtained by this method presented a fine porous structure, resulting in greater specific surface area compared to those of β-maltose monohydrate and anhydrous β-maltose obtained by vacuum drying (Mβh). The crystal transformation presumably consisted of two steps: dehydration reaction from the hydrous to amorphous forms and crystal formation from the amorphous forms to the noble anhydrous form. The kinetics of these reactions were determined by thermal analysis using Jander’s equation and Arrhenius plots. The overall activation energies of the dehydration reaction and the formation of anhydrous maltose were evaluated to be 100 and 90kJ/mol, respectively.

Varenicline L-tartrate Crystal Forms: Characterization Through Crystallography, Spectroscopy, and Thermodynamics

This research utilized crystallographic, spectroscopic, and thermal analysis data to assess the thermodynamic stability relationship between the three known crystal forms of Varenicline L-tartrate. Of the two anhydrous forms (Forms A and B), Form B was determined to be the stable form at 0 K based on its calculated true density, hydrogen bonding in the crystal lattice, and application of the IR rule. Form A has a higher melting point and higher solubility at room temperature as compared to Form B, indicating that these forms are enantiotropically related. Application of the eutectic-melting method enabled accurate determination of the transition temperature (63 degrees C), with Form B as the stable anhydrous form at room temperature. The stability relationships between the anhydrous polymorphs and the monohydrate (Form C) were assessed through exposure of the anhydrous forms to a range of water vapor pressures at room temperature. A phase boundary was identified, with the monohydrate being the thermodynamically stable form above critical water activity values of 0.85 and 0.94 for Forms A and B, respectively. These results provide a better understanding of the form stability as it relates to normal manufacturing and storage conditions for the active pharmaceutical ingredient and drug product.

The effect of particle size on the dehydration/rehydration behaviour of lactose

Ethanolic suspensions of spray dried and micronized alpha lactose monohydrate (Lα·H 2O) with average particle size between 3 and 200 μm, have been prepared and their dehydration behaviour was investigated by 13C CP-MASNMR spectroscopy. Sub-micron lactose suspension prepared by a novel high pressure homogenisation method has been compared with the standard ethanolic suspensions of Lα·H 2O prepared by reflux or static room temperature methods. In all cases, suspensions were shown to contain the stable anhydrous form of lactose (Lα S). Several approaches were employed to remove ethanol from these suspensions and the resulting dry lactose powders were then analysed by FT-IR, PXRD and SEM to evaluate the effect of drying procedure on type and distribution of lactose polymorphs and particle size. For samples with mean particle size greater than 1 μm, the stable anhydrous polymorphic form of lactose was retained on removal of the ethanol, although differences in the morphology and particle size of the crystals were apparent depending on method of suspension formation. Sub-micron Lα S, while stable in dry conditions, has been shown to be less stable to atmospheric water vapour than Lα S with particle size between 3 and 200 μm.

Rapid conversion of API hydrates to anhydrous forms in aqueous media

Three anhydrous polymorphs, a monohydrate and a dihydrate of an active pharmaceutical ingredient, N-{[(5S)-3-(4-{6-[(1R,5S)-6-cyano-3-oxabicyclo[3.1.0]hex-6-yl]pyridin-3-yl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (Compound 1), have been crystallized and characterized. Slurry experiments and thermal data have been used to determine their relative thermodynamic stability. The hydrates of Compound 1 were found to be less stable than the most stable anhydrous Form I and converted into Form I in water within 15 min. The rate of conversion in a dry state was found to depend on the relative humidity (RH) and was highest at the two RH extremes examined, 5% and 97.5% RH. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4111–4118, 2009

Multiple approaches to pharmaceutical polymorphism investigation—A case study

Polymorph screening of Compound A, an investigational drug, revealed two anhydrous polymorphs (Forms I and II) and two monohydrates (Forms III and IV) of this pharmaceutical solid. The physiochemical properties of the four forms were characterized by thermal analysis, hot-stage microscopy, equilibrium solubility and intrinsic dissolution rate measurements, and X-ray powder diffraction. Inter-conversion relationship of the four forms was fully elucidated. Thermodynamic stability relationship was inferred from melting data for Form I and Form II and evaluated by van’t Hoff plot for Form III and Form IV. Form I and Form III were found to be the more stable anhydrous and hydrate form, respectively. Anhydrous Form I was selected for further pharmaceutical development.

Structure determination of the stable anhydrous phase of α-lactose from X-ray powder diffraction

The stable anhydrous form of alpha-lactose has been obtained by the dehydration of alpha-lactose monohydrate in methanol. An X-ray powder diffraction pattern was recorded at room temperature with a laboratory diffractometer equipped with an INEL curved sensitive detector CPS120. The starting structural model of this form was found by a Monte-Carlo simulated annealing method. The structure was obtained through Rietveld refinements and the minimization of crystalline energy for the localization of the H atoms of the hydroxyl groups. Soft restraints were applied to bond lengths and angles. Networks of O-H...O hydrogen bonds account for the crystalline cohesion. A comparison is made between the hydrogen-bond networks of this form and those of the monohydrate and hygroscopic anhydrous forms of alpha-lactose.

Structural analysis of polymorphism and solvation in tranilast

Five polymorphic forms of tranilast were characterized by thermal, diffractometric, and spectroscopic techniques. The crystal structures of the most stable anhydrous form (Form I), a chloroform solvate, and a dichloromethane solvate were determined from single‐crystal X‐ray analysis. Two additional anhydrous forms of tranilast (Forms II and III) were also studied, but were not amenable to SCXRD. All five forms were also analyzed using solid‐state nuclear magnetic resonance, Fourier transform infrared, and Fourier transform‐Raman spectroscopy, and thermal methods. From the trends observed in the crystal structures and the spectral data, some conclusions can be made about hydrogen bonding, molecular conformation, and crystal packing differences in the polymorphs and solvates. Form II was found to be a spectroscopically distinctive polymorph that is probably missing an important intramolecular hydrogen bond coupled with a conformational change. In contrast, Form III was found to be more similar to the crystallographically characterized forms, and is more likely a packing and hydrogen‐bonding polymorph with a weakened intermolecular hydrogen‐bonding interaction relative to the other forms. From a pharmaceutical development perspective, it is shown that although the anhydrous forms of tranilast have similar thermal properties, they can be reliably distinguished by spectroscopic methods. © 2005 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:651–665, 2005

Anhydrates and Hydrates of Olanzapine: Crystallization, Solid-State Characterization, and Structural Relationships

Olanzapine, a novel benzodiazepine agent used in the treatment of schizophrenia and related psychoses, crystallizes in 25+ crystal forms, seven of which are pharmaceutically relevant: three anhydrates (I−III), three dihydrates (B, D, and E), and a higher hydrate. X-ray crystal structures of the thermodynamically stable anhydrous form (I), two dihydrates (B and D), a higher hydrate, and a Rietveld-refined structure of dihydrate E have permitted a detailed analysis of the conformational, hydrogen bonding, and crystal packing preferences of olanzapine. The symmetry and hydrogen-bonding interactions in the crystal forms have also been characterized by 13C and 15N CP/MAS NMR spectroscopy. Using the crystallographic and spectroscopic data, significant structural relationships have been identified between the crystal forms of olanzapine. The present study demonstrates the utility of integrating crystallography, spectroscopy, and crystal modeling in detailed structural investigations of polymorphism (and solvate...

Dehydration Mechanism and Crystallisation Behaviour of Lactose

The dehydration mechanism of α-lactose monohydrate was investigated by several techniques and interpreted on the basis of structural data. Whatever the dehydration conditions (heating or use of hygroscopic organic solvents), the departure of water molecules occurs cooperatively in channels parallel to the c axis of the initial structure. Subsequently, the reorganization leads to the closest packing (hygroscopic metastable form, LαH) under heating or to the stable anhydrous form (LαS), probably via a nucleation and growth process in ethanol. The use of acetone as dehydrating solvent on single crystals of α-lactose monohydrate led to the unexpected formation of single crystals of the anomeric β-lactose at room temperature, from which the crystal structure of β-lactose could be accurately re-determined. Recrystallization experiments of anhydrous lactose allowed to prepare N-methylpyrrolidinone and DMSO solvates of α-lactose.

Crystallisation solvent induced solid-state and particulate modifications of nitrofurantoin

Nitrofurantoin has been batch crystallised from both formic acid and formic acid/water (2:1). Powder X-ray analyses indicated different crystal structures. Thermal analysis (DSC and TGA) data showed that this was due to the formation of a monohydrate in the sample crystallised from the binary solvent. Production of the monohydrate was attributed to changes in the interactions between nitrofurantoin and the solvent systems during crystallisation. On drying the monohydrate, a stable anhydrous form was obtained. Marked differences in crystal habit of the two samples, as shown by scanning electron microscopy and image analysis, were maintained. The sample crystallised from formic acid had tabular crystal habit whilst that from formic acid/water was needle-like. This habit modification was thought to be associated with preferential adsorption of the water molecules by polar crystal faces, thus inhibiting their growth.

Dimorphism of β- n-oxalyl- l-α, β-diaminopropionic acid

The neurotoxic non-protein amino acid, β- N-oxalyl- l-α, β-diaminopropionic acid (β-ODAP) exists in two crystalline modifications; a metastable monohydrate and a thermodynamically stable anhydrous form. Reproducible methods for preparing each polymorph are described and their structures are discussed on the basis of their general physical characteristics and their IR spectra and X-ray powder patterns. The ionic properties of the amino acid were studied in solution and revised p Kina values for the two carboxyl functions are reported.

Effect of Various Alcohols on Lactose

The types of lactose resulting from treatment with various alcohols were studied. Conversion of α-hydrate to the stable anhydrous form of lactose was similar in ethanol, propanol, butanol, and isobutanol; the reaction was slow at room temperature but at refluxing temperature was usually complete in 1h. The reaction was slowed by increasing moisture content in the alcohol, becoming inhibited at 2 to 2.5% moisture, depending on whether the moisture was added or came from the water of crystallization. Converson from α-hydrate to stable-α slowed as the alcohol chain length increased, particularly in the presence of moisture. The product also became more variable.The product of concentrated lactose solution added to methanol contained only anhydrous lactose but at the normal alpha:beta ratio. With moisture content above 10%, some α-hydrate was formed, but at a normal ratio, suggesting either insufficient time and/or insufficient moisture for mutarotation. Above 15% moisture, α-hydrate increased until at 35% moisture α-hydrate became the entire product. Product composition could be controlled by starting with either alpha-or beta-lactose and allowing mutarotation to produce the desired composition before the solution was added to methanol.An explanation is proposed for the transient milldness that sometimes results when lactose solutions and organic solvents are mixed: the milldness is due to the formation of minute α-stable crystals temporarily formed at critical amounts of lactose, moisture, and solvent, with too much moisture preventing formation because of high solubility, and too much solvent resulting in permanent precipitation.

Effect of Methanol on the Various Forms of Lactose

Methanol is suitable for removal of the water of crystallization from alpha-lactose hydrate to form new crystals of stable anhydrous alpha-lactose. The crystalline product is more bulky than the hydrated lactose and is not hygroscopic, as is the anhydrous form produced by heat and vacuum. Conversion from alpha-hydrate to the new anhydrous form can be completed in 1h at refluxing temperature (64.6C) at all proportions of alpha-lactose hydrate to dry methanol or in methanol containing up to 5% moisture.The rate of production of the anhydrous form follows a first-order reaction at room temperature in methanol. Formation is rapid at first while the methanol is dry, but as the solvent is diluted by the water of crystallization from alpha-hydrate, the reaction gradually slows. For complete conversion, a ratio of 1 part alpha-hydrate to at least 15 parts dry methanol is required for 2h at room temperature. This ratio of 1:15 provides the maximum limit of moisture (.4%) in the final solution where the rate remains maximum at room temperature. Between .4 and 2.0% moisture retards nucleus formation of the new crystal. Therefore, an induction period is observed since the reaction cannot proceed until nuclei develop. Seeding eliminates the induction period by furnishing nuclei. The conversion reaction ceases when moisture is increased above 2%.The regular (hygroscopic) anhydrous alpha-lactose also is converted by methanol to the stable anhydrous form, indicating it is the more stable in low moisture methanol. The new crystal form is produced even in dry methanol, showing that moisture is unnecessary for the crystallization. Beta-lactose, however, is not changed by the action of methanol at either room or boiling temperature.Noncrystalline lactose (lactose glass) readily dissolves in methanol forming a supersaturated solution which quickly crystallizes as an anhydrous mixture with a normal equilibrium ratio of 60% beta-lactose and 40% alpha-lactose. This same ratio is produced when lactose glass is added to methanol containing no more than 10% moisture; above this moisture, alpha-lactose hydrate will form. As the moisture content is increased further, the amount of alpha-hydrate increases until at 35% moisture content the entire product is alpha-hydrate.Contrary to aqueous solutions, beta-lactose does not interfere with crystallization of alpha-lactose in methanol.