A thermodynamically consistent phase diagram of a trimorphic pharmaceutical, l-tyrosine ethyl ester, based on limited experimental data.

Crystalline polymorphs possess different physical properties, and phase changes between those polymorphs may affect the properties of engineered materials such as drugs. This is very well illustrated by the large effort that is put into the capability to predict phase behaviour of pharmaceuticals to avoid the unexpected appearance of different crystal forms. Much progress has been made, but one of the remaining challenges is (the accuracy in) the prediction of phase behaviour as a function of temperature. Obviously, predictions should at a certain point be verified against experimental data; however, it may not always be easy to elucidate the phase behaviour of a given compound experimentally, because thermodynamically and kinetically controlled phenomena occur in a convoluted fashion in experimental data. The present paper discusses the trimorphism of l-tyrosine ethyl ester as an example case of how experimental data in combination with the thermodynamic tenets lead to a consistent phase diagram, which can be used as the basis for pharmaceutical formulations and for comparison with polymorph predictions by computer. The positions of the two-phase equilibria I-II, I-III, and I-L have been obtained experimentally. Using the Clapeyron equation and the alternation rule, it has been shown how the positions of the other equilibria II-L, III-L, and II-III can be deduced in combination with the stability rankings of the phases and the phase equilibria. The experimental data have been obtained by synchrotron X-ray diffraction, Raman spectroscopy, and thermal analysis as a function of pressure and temperature. Furthermore, laboratory X-ray diffraction as a function of temperature and differential scanning calorimetry have been used. At room temperature, form II is the most stable phase, which remains stable with increasing pressure, as it possesses the smallest specific volume. Form I becomes stable above 33 °C (306 K), but with increasing pressure it turns into form III. On thermodynamic grounds, form III is expected to have a stable domain at very low temperatures.

An Integrated View of the Influence of Temperature, Pressure, and Humidity on the Stability of Trimorphic Cysteamine Hydrochloride.

Understanding the phase behavior of pharmaceuticals is important for dosage form development and regulatory requirements, in particular after the incident with ritonavir. In the present paper, a comprehensive study of the solid-state phase behavior of cysteamine hydrochloride used in the treatment of nephropathic cystinosis and recently granted orphan designation by the European Commission is presented employing (high-pressure) calorimetry, water vapor sorption, and X-ray diffraction as a function of temperature. A new crystal form (I2/a, form III) has been discovered, and its structure has been solved by X-ray powder diffraction, while two other crystalline forms are already known. The relative thermodynamic stabilities of the commercial form I and of the newly discovered form III have been established; they possess an overall enantiotropic phase relationship, with form I stable at room temperature and form III stable above 37 °C. Its melting temperature was found at 67.3 ± 0.5 °C. Cysteamine hydrochloride is hygroscopic and immediately forms a concentrated saturated solution in water with a surprisingly high concentration of 47.5 mol % above a relative humidity of 35%. No hydrate has been observed. A temperature-composition phase diagram is presented that has been obtained with the unary pressure-temperature phase diagram, measurements, and calculations. For development, form I would be the best form to use in any solid dosage form, which should be thoroughly protected against humidity.

Fluorescence properties reinforced by proton transfer in the salt 2,6-diaminopyridinium dihydrogen phosphate.

Luminescent materials have many interesting applications, but it remains difficult to control the luminescence of organic materials and in particular to retain the same luminescence in solution and in the solid state, a property of interest for various imaging applications. In the present work, the fluorescent properties of the salt of 2,6-diaminopyridinium with dihydrogen phosphate have been explored. As a result of proton transfer from phosphoric acid to the pyridine nitrogen and the stabilizing effect of the two primary amines at the positions ortho to the pyridine nitrogen, the band gap between the HOMO and the LUMO is considerably diminished in comparison with that in 2,6-diaminopyridine. This is confirmed by a red shift in its absorption spectrum. Because protonation is retained in aqueous solution, the dissolved 2,6-diaminopyridinium dihydrogen phosphate salt retains a similar fluorescent spectrum as in the solid state. The crystals have been studied by single-crystal X-ray diffraction; FTIR, Raman, UV-vis-NIR, and luminescence spectroscopy; HOMO-LUMO calculations using DFT; and thermal analysis. The compound provides an example of a supramolecular motif that controls the crystal structure and the luminescence properties. In addition, the crystal exhibits negligible thermal expansion over a temperature interval of 150 °C. In short, 2,6-diaminopyridinium dihydrogen phosphate is an interesting compound for the design of luminescent devices.

Liquid-liquid miscibility gaps in drug-water binary systems: crystal structure and thermodynamic properties of prilocaine and the temperature-composition phase diagram of the prilocaine-water system.

EMLA cream, a "eutectic mixture of local anesthetics", was developed in the early 1980s by Astra Pharmaceutical Production. The mixture of anesthetics containing lidocaine, prilocaine, and water is liquid at room temperature, which is partly due to the eutectic equilibrium between prilocaine and lidocaine at 293 K, as was clear from the start. However, the full thermodynamic background for the stability of the liquid and its emulsion-like appearance has never been elucidated. In the present study of the binary system prilocaine-water, a region of liquid-liquid demixing has been observed, linked to a monotectic equilibrium at 302.4 K. It results in a prilocaine-rich liquid containing approximately 0.7 mol fraction of anesthetic. Similar behavior has been reported for the binary system lidocaine-water (Céolin, R.; et al. J. Pharm. Sci. 2010, 99 (6), 2756-2765). In the ternary mixture, the combination of the monotectic equilibrium and the above-mentioned eutectic equilibrium between prilocaine and lidocaine results in an anesthetic-rich liquid that remains stable below room temperature. This liquid forms an emulsion-like mixture in the presence of an aqueous solution saturated with anesthetics. Physical properties and the crystal structure of prilocaine are also reported.

Solid-solid Phase Transitions between Crystalline Polymorphs of Organic Materials.

In this review, the analysis of solid-solid phase transitions between crystalline polymorphs of organic molecules is discussed. Although active pharmaceutical ingredients (APIs) are the scope of the review, whether an organic molecule has a biological activity or not does not particularly define its interactions in the crystalline state. Therefore, other small organic molecules have been included in this analysis and in certain cases, polymers have been discussed too. The focus of the review is on experimental analysis; however, a section on computational and theoretical methods has been added because these methods are becoming important and are obviously helpful in understanding for example transition mechanisms because the results can be easily visualized. The following aspects of solid-solid phase transitions between crystalline structures are presented in this review. The thermodynamics of phase transitions between polymorphs involving thermodynamic equilibrium and the variables temperature and pressure closely linked to the Gibbs free energy are discussed. The two main transition mechanisms in the organic crystalline solid, displacive and concerted, are discussed. Experimental methods that are used to understand the mechanisms and thermodynamic equilibrium between different polymorphs of an API are reviewed. The switching of polymorph properties is discussed, and heat storage and release are reviewed as it is one of the main applications of solid-state phase transitions. Of interest for the control of drug products, constraining phase transitions has been reviewed, as it may help increase the bioavailability of an API by using metastable phases. Finally, second order phase transitions of organic materials, which appear to be rare, are discussed. It can be concluded that although the general theory of polymorphism and phase transitions is well understood, how it works out for a specific molecule remains difficult to predict.

The Phase Diagram of the API Benzocaine and Its Highly Persistent, Metastable Crystalline Polymorphs.

The availability of sufficient amounts of form I of benzocaine has led to the investigation of its phase relationships with the other two existing forms, II and III, using adiabatic calorimetry, powder X-ray diffraction, and high-pressure differential thermal analysis. The latter two forms were known to have an enantiotropic phase relationship in which form III is stable at low-temperatures and high-pressures, while form II is stable at room temperature with respect to form III. Using adiabatic calorimetry data, it can be concluded, that form I is the stable low-temperature, high-pressure form, which also happens to be the most stable form at room temperature; however, due to its persistence at room temperature, form II is still the most convenient polymorph to use in formulations. Form III presents a case of overall monotropy and does not possess any stability domain in the pressure-temperature phase diagram. Heat capacity data for benzocaine have been obtained by adiabatic calorimetry from 11 K to 369 K above its melting point, which can be used to compare to results from in silico crystal structure prediction.

Mixed Polymeric Micelles for Rapamycin Skin Delivery.

Facial angiofibromas (FA) are one of the most obvious cutaneous manifestations of tuberous sclerosis complex. Topical rapamycin for angiofibromas has been reported as a promising treatment. Several types of vehicles have been used hitherto, but polymeric micelles and especially those made of d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) seem to have shown better skin bioavailability of rapamycin than the so far commonly used ointments. To better understand the influence of polymeric micelles on the behavior of rapamycin, we explored it through mixed polymeric micelles combining TPGS and poloxamer, evaluating stability and skin bioavailability to define an optimized formulation to effectively treat FA. Our studies have shown that TPGS improves the physicochemical behavior of rapamycin, i.e., its solubility and stability, due to a strong inclusion in micelles, while poloxamer P123 has a more significant influence on skin bioavailability. Accordingly, we formulated mixed-micelle hydrogels containing 0.1% rapamycin, and the optimized formulation was found to be stable for up to 3 months at 2-8 °C. In addition, compared to hydroalcoholic gel formulations, the studied system allows for better biodistribution on human skin.

Polymorphism of benzylthiouracil, an active pharmaceutical ingredient against hyperthyroidism.

The crystal structures of dimorphic benzylthiouracil, a drug against hyperthyroidism, have been redetermined and the atom coordinates of the two independent molecules of form I have been obtained for the first time. The dimorphism convincingly demonstrates the conformational versatility of the benzylthiouracil molecule. It has been established through calorimetric studies that the low-temperature form II transforms endothermically (ΔII→IH = 5.6(1.5) J g-1) into form I at 405.4(1.0) K. The high-temperature form I melts at 496.8(1.0) K (ΔI→LH = 152.6(4.0) J g-1). Crystallographic and thermal expansion studies show that form II is denser than form I, leading to the conclusion that the slope of the II-I equilibrium curve in the pressure-temperature phase diagram is positive. It follows that this dimorphism corresponds to a case of overall enantiotropic behaviour, which implies that both solid phases possess their own stable phase region irrespective of the pressure. Moreover, form II is clearly the stable polymorph under ambient conditions.

Crystalline tetrazepam as a case study on the volume change on melting of molecular organic compounds.

The volume change on melting is a rarely studied quantity and it is not well understood even if it must reflect the changes in interaction between the solid and the liquid state. It is part of the solid-state information for materials and pharmaceuticals and it is important for the reliability of polymorph stability study results. Using the crystal structure of monoclinic tetrazepam at 150 K and at room temperature, in addition to powder X-ray diffraction as a function of the temperature, the specific volume of tetrazepam has been determined over a large temperature domain. In combination with a pressure-temperature curve for the melting of tetrazepam, its volume change on melting could be determined. With this information and previous data from the literature, the assumption that the volume of the solid increases on average with 11% on melting has been investigated. It can be concluded that this value is not constant; however so far, no simple relationship has been found to relate the solid state to its volume change on melting and using 11% remains best practice. A comparison of the tetrazepam crystal structure with diazepam and nordiazepam has been provided too.

The solid state of anti-inflammatory morniflumate diniflumate: A cocrystalline salt.

Morniflumate diniflumate, a molecular compound involving niflumic acid and its ß-morpholino ethyl ester (morniflumate) in the mole ratio 2:1, is found to crystallize in a triclinic P - 1 space group with a unit-cell volume of 2203.4(5) Å3. It is a cocrystal between a morniflumate+ niflumate- salt and a neutral niflumic acid molecule. The co-crystalline salt forms endothermically with a positive excess volume and it melts incongruently at 382.3(8) K. Differential scanning calorimetry executed at heating rates above 20 K⋅min-1, leads to congruent melting at 387.8(9)K with an enthalpy change of ΔfusH = 80(2) J g-1. The rare occurrence that incongruent and congruent melting can be observed for the same cocrystal may be due to the conformational versatility of the niflumic acid molecule and its slow conversion between the different conformations due to weak intramolecular hydrogen bonding.

The phase relationship between the pyrazinamide polymorphs α and γ.

Pyrazinamide is an active pharmaceutical compound for the treatment of tuberculosis. It possesses at least four crystalline polymorphs. Polymorphism may cause solubility problems as the case of ritonavir has clearly demonstrated; however, polymorphs also provide opportunities to improve pharmaceutical formulations, in particular if the stable form is not very soluble. The four polymorphs of pyrazinamide constitute a rich system to investigate the usefulness of metastable forms and their stabilization. However, despite the existence of a number of papers on the polymorphism of pyrazinamide, well-defined equilibrium conditions between the polymorphs appear to be lacking. The main objectives of this paper are to establish the temperature and pressure equilibrium conditions between the so-called α and γ polymorphs of pyrazinamide, its liquid phase, and vapor phase and to determine the phase-change inequalities, such as enthalpies, entropies, and volume differences. The equilibrium temperature between α and γ was experimentally found at 392(1) K. Moreover, vapor pressures and solubilities of both phases have been determined, clearly indicating that form α is the more stable form at room temperature. High-pressure thermal analysis and the topological pressure-temperature phase diagram demonstrate that the γ form is stabilized by pressure and becomes stable at room temperature under a pressure of 260 MPa.

Does the trihydrate of atorvastatin calcium possess a melting point?

To decide whether an active pharmaceutical ingredient can be used in its amorphous form in drug formulations, often the glass transition is studied in relation to the melting point of the pharmaceutical. If the glass transition temperature is high enough and found relatively close to the melting point, the pharmaceutical is considered to be a good glass former. However, it is obviously important that the observed melting point and glass transition involve exactly the same system, otherwise the two temperatures cannot be compared. Although this may seem trivial, in the case of hydrates, where water may leave the system on heating, the composition of the system may not be evident. Atorvastatin calcium is a case in point, where confusing terminology, absence of a proper anhydrate form, and loss of water on heating lead to several doubtful conclusions in the literature. However, considering that no anhydrate crystal has ever been observed and that the glass transition of the anhydrous system is found at 144 °C, it can be concluded that if the system is kept isolated from water, the chances that atorvastatin calcium crystallises at room temperature is negligible. The paper discusses the various thermal effects of atorvastatin calcium on heating and proposes a tentative binary phase diagram with water.

Physical and chemical stability of a generic etoposide formulation as an alternative to etoposide phosphate.

The generic Mylan® etoposide (ETP) has been investigated as an alternative for Etopophos®, in part due to a global shortage of the latter. The generic alternative is different both in its formulation and in its very limited stability (6 h at 25 °C against 4 days for Etopophos®) once reconstituted in ready-to-use chloride or glucose solutions. Its intrinsic stability has been thoroughly studied under various conditions. Two degradation products resulting from hydrolysis were characterized by LC-HR-MSn and supported by density functional theory calculations of the frontier molecular orbitals energies, molecular electrostatic potential mapping, and Mulliken charge analysis. Chemical degradation increases with temperature and can be fitted to a zero order kinetic model with a half-life of 119 days and a kinetic constant of 0.0028 mM day-1. Precipitation was only observed in solutions at 5 °C and -20 °C indicating that at these temperatures the reconstituted solutions are thermodynamically metastable. In conclusion, ETP at concentrations of 0.68 and 1 mM prepared and stored at 25 °C under good manufacturing practices remained unchanged over a period of 21 days irrespective of the nature of the solvents or the type of container.

[60]Fullerene for Medicinal Purposes, A Purity Criterion towards Regulatory Considerations.

Since the early nineties countless publications have reported promising medicinal applications for [60]fullerene (C60) related to its unparalleled affinity towards free radicals. Yet, until now no officially approved C60-based drug has reached the market, notably because of the alleged dangers of C60. Nevertheless, since the publication of the effects of C60 on the lifespan of rodents, a myriad of companies started selling C60 worldwide for human consumption without any approved clinical trial. Nowadays, several independent teams have confirmed the safety of pure C60 while demonstrating that previously observed toxicity was due to impurities present in the used samples. However, a purity criterion for C60 samples is still lacking and there are no regulatory recommendations on this subject. In order to avoid a public health issue and for regulatory considerations, a quality-testing strategy is urgently needed. Here we have evaluated several analytical tools to verify the purity of commercially available C60 samples. Our data clearly show that differential scanning calorimetry is the best candidate to establish a purity criterion based on the sc-fcc transition of a C60 sample (Tonset ≥ 258 K, ∆sc-fccH ≥ 8 J g-1).

Polymorphism of spironolactone: An unprecedented case of monotropy turning to enantiotropy with a huge difference in the melting temperatures.

Spironolactone form I melts at about 70 degrees lower than form II, which is very unusual for two co-existing polymorphs. The phase relationships involving this unprecedented case of dimorphism have been investigated by constructing a topological pressure-temperature phase diagram. The transition from polymorph I to polymorph II is unambiguously exothermic while it is accompanied with an increase in the specific volume. This indicates that the dP/dT slope of the I-II equilibrium curve is negative. The convergence of the melting equilibrium lines at high pressure leads to a topological P-T diagram in which polymorph I possesses a stable phase region at high pressure. Thus, forms I and II are monotropically related at ordinary pressure and turn to an enantiotropic relationship at high pressure. Given that polymorph I is the densest form, it negates the rule of thumb that the densest form is also the most stable form at room temperature, similar to the case of paracetamol.

The Pressure-Temperature Phase Diagram of Metacetamol and Its Comparison to the Phase Diagram of Paracetamol.

Understanding the polymorphic behavior of active pharmaceutical ingredients is important for formulation purposes and regulatory reasons. Metacetamol is an isomer of paracetamol and it similarly exhibits polymorphism. In the present article, it has been found that one of the polymorphs of metacetamol is only stable under increased pressure, which has led to the conclusion that metacetamol like paracetamol is a monotropic system under ordinary (= laboratory) conditions and that it becomes enantiotropic under pressure with the I-II-L triple point coordinates for metacetamol TI-II-L = 535 ± 10 K and PI-II-L = 692 ± 70 MPa. However, whereas for paracetamol the enantiotropy under pressure can be foreseen, because the metastable polymorph is denser, in the case of metacetamol this is not possible, as the metastable polymorph is less dense than the stable one. The existence of the stability domain for the less dense polymorph of metacetamol can only be demonstrated by the construction of the topological phase diagram as presented in this article. It is a delicate interplay between the specific volume differences and the enthalpy differences causing the stability domain of the less dense polymorph to be sandwiched between the denser polymorph and the liquid. Metacetamol shares this behavior with bicalutamide and fluoxetine nitrate.