Summary Chloroprocaine hydrochloride (2-CPCHC) is a local anaesthetic agent of the ester type preferentially used for epidural anaesthesia. The compound, official in the USP, was found to exist in two polymorphic crystal forms which have been characterized by thermomicroscopy, differential scanning calorimetry (DSC), pycnometry, FTIR-, FT-Raman-spectroscopy as well as X-ray powder diffractometry. Based on these data the relative thermodynamic stability of the two forms was determined and is represented in a semi-schematic energy/temperature diagram. Mod. I° is the thermodynamically stable form at room temperature. This form is present in commercial products and can be crystallized from ethanol. Mod. II can be obtained by annealing the supercooled melt in a temperature range between 100 and 130°C. Upon heating mod. II exhibits an exothermic phase transition (ΔtrsHII-I: -5.0±0.5 kJ mol-1) at about 134°C to mod. I° (melting point 175°C, ΔfusHI: 46.6±0.6 kJ mol-1). The exothermic transformation of mod. II to mod. I° confirms that mod. I° is thermodynamically stable in the entire temperature range (heat of transition rule) whereas mod. II is monotropically related to mod. I°, i.e. is metastable at all temperatures below its melting point. Mod. II is of low kinetic stability at room temperature and the transformation to mod. I° starts within a few minutes at room temperature. The N-H band in the infrared spectrum of mod. I° (3433 cm-1) lies at significantly higher wavenumbers than that of mod. II (3413 cm-1) indicating differences in the hydrogen bonding arrangement. Furthermore, the measured density of mod. I° is lower than the density of mod. II and thus both, the IR- and the density-rule are violated in this polymorphic system.
Authors:D. Giron, Ch. Goldbronn, M. Mutz, S. Pfeffer, Ph. Piechon, and Ph. Schwab
Manufacturing processes may involve the presence of water in the crystallization of the drug substance or in manufacturing
or in the composition of the drug product through excipients. Dehydration steps may occur in drying, milling, mixing and tabletting
processes. Furthermore, drug substances and drug products are submitted to different temperatures and relative humidities,
due to various climatic conditions giving rise to unexpected hydration or dehydration aging phenomena. Therefore the manufacture
and the characterization of hydrates is part of the study of the physical properties of drug substances.
Several hydrates and even polymorphic forms thereof can be encountered. Upon dehydration crystal hydrates may retain more
or less their original crystal structure, they can lose crystallinity and give anamorphous phase, they can transform to crystalline
less hydrated forms or to crystalline anhydrous forms.
The proper understanding of the complex polyphasic systemhydrates–polymorphs–amorphous state needs several analytical methods.
The use of techniques such as DSC-TG, TG-MS, sorption-desorption isotherms, sub-ambient experiments, X-ray diffraction combined
with temperature or moisture changes as well as crystal structure and crystal modelling in addition to solubilities and dissolution
experiments make interpretation and quantitation easier as demonstrated with some typical examples.
Authors:M. Cirri, F. Maestrelli, S. Furlanetto, and P. Mura
Natural crystalline (α-, β-, γ-) and amorphous derivative (hydroxypropyl-β- and methyl-β) cyclodextrins were selected as potential
carriers for obtaining, through a co-grinding technique, a stable activated amorphous form of glyburide with improved dissolution
properties. Differential scanning calorimetry (DSC) was used to investigate solid-state modifications of the drug induced
by co-grinding with the selected carriers in a high energy vibrational micro-mill. X-ray powder diffraction and FTIR spectroscopy
were employed as additional techniques to support DSC data. Equimolar drug : cyclodextrin physical mixtures were co-ground
for different times (up to 60 min) at constant vibration frequency (24 Hz). A progressive drug amorphization with increasing
grinding time was observed in all binary systems, but, interestingly, different degrees of sensitivity to the mechanical-chemical
activation were evident. In fact, blends with natural cyclodextrins, despite the initial higher crystallinity than those with
the amorphous derivatives, required the same or shorter co-grinding times (60 min) to achieve complete drug amorphization.
Stability studies indicated no appreciable drug recrystallization in co-ground products after 4 months storage in sealed containers
at 25°C or 1 month at 25°C and 75% RH. No stability differences were detected between products with natural or derivative
cyclodextrins. The results accounted for the suitability of cyclodextrin co-grinding technique to obtain and stabilize glyburide
in the activated amorphous form.
Authors:L. Bernardi, P. Oliveira, F. Murakami, M. Silva, S. Borgmann, and S. Cardoso
The thermal analytical study of venlafaxine hydrochloride, a third generation antidepressant, was investigated using thermogravimetry
(TG) and differential scanning calorimetry (DSC). The DSC curves have shown a sharp endothermic event at 211 °C and TG demonstrated
a single stage of mass loss between 254 and 283 °C. Solid-state characterization was carried out by DRIFT, SEM, and XRPD demonstrating
the drug physicochemical properties including crystallinity. Drug-excipient compatibility studies investigated by DSC have
shown a possible physical interaction of the drug with magnesium stearate, microcrystalline cellulose and starch. Nevertheless,
these results where not confirmed by DRIFT and SEM analyses.
Authors:Shun-Li Wang, Yu-Chiau Wong, Wen-Ting Cheng, and Shan-Yang Lin
Solidstatecharacterization and physicochemical property of the active pharmaceutical ingredients (APIs) are fundamental elements in the pharmaceutical development from the beginning of drug discovery to the final
Authors:Gabriel de Araujo, Dalva de Faria, Márcio Zaim, Flávio de Souza Carvalho, Fabio de Andrade, and Jivaldo Matos
Tibolone polymorphic forms I (monoclinic) and II (triclinic) have been prepared by recrystallization from acetone and toluene,
respectively, and characterized by different techniques sensitive to changes in solid state, such as polarized light microscopy,
X-ray powder diffractometry, thermal analysis (TG/DTG/DSC), and vibrational spectroscopy (FTIR and Raman microscopy). The
nonisothermal decomposition kinetics of the obtained polymorphs were studied using thermogravimetry. The activation energies
were calculated through the Ozawa’s method for the first step of decomposition, the triclinic form showed a lower Ea (91 kJ mol−1) than the monoclinic one (95 kJ mol−1). Furthermore, Raman microscopy and DSC at low heating rates were used to identify and follow the thermal decomposition of
the triclinic form, showing the existence of three thermal events before the first mass loss.
Authors:G. Bruni, V. Berbenni, C. Milanese, A. Girella, P. Cofrancesco, G. Bellazzi, and A. Marini
In this work the solid-state characterization of anhydrous D-mannitol has been performed: α and β modifications can be distinguished only by XRPD and FTIR as they show melting temperature
and enthalpy that are the same within the standard deviation. The understanding of the thermal behaviour of the δ form (obtained
by re-crystallization in acetone) has required XRPD experiments performed at variable temperature. This form during heating
undergoes a solid phase transition to α modification. By cooling a melted sample, under a wide range of experimental conditions,
a very fast crystallization occurs. Independently of the starting crystal form (β or δ form), the re-crystallization of D-mannitol from melt always leads to α form.
Authors:P. Oliveira, H. Stulzer, L. Bernardi, S. Borgmann, S. Cardoso, and M. Silva
In the present work, the thermal decomposition of sibutramine hydrochloride monohydrate (SBT) (an appetite suppressant agent)
was studied using differential scanning calorimetry (DSC) and thermogravimetry/derivative thermogravimetry (TG/DTG). Solid-state
characterization was carried out by diffuse reflectance infrared fourier transform spectroscopy (DRIFT), scanning electron
microscopy (SEM) and X-ray powder diffraction (XRPD). Isothermal and non-isothermal methods were employed to determine the
kinetic data of decomposition process. From isothermal experiments, activation energy (Ea) can be obtained from slope of ln t versus 1/T, and the value obtained was 96.06 and 101.43 kJ mol−1 in N2 and air atmospheres, respectively. For non-isothermal method Ea can be obtained from plot of logarithms of heating rates, as a function of inverse of temperature, resulting in a value
of 96.56 and 98.22 kJ mol−1 in N2 and air atmospheres, respectively. The compatibilities of several commonly used pharmaceutical excipients (microcrystalline
cellulose, magnesium stearate, colloidal silicon dioxide, lactose monohydrate) and empty hard-gelatin capsules with SBT were
evaluated using DSC. The 1:1 physical mixtures of these excipients with SBT showed physical interaction of the drug with magnesium
stearate. On the other hand, DRIFT results did not evidence any chemical modifications.
Authors:Luciana Malpezzi, Elisabetta Maccaroni, Giordano Carcano, and Gianpiero Ventimiglia
Sodium Ibandronate (NaIb) belongs to the nitrogen-containing bisphosphonates drugs, used as anti-resorptive medications for the treatment of osteoporosis. The crystalline form of NaIb monohydrate was observed to undergo reversible thermal dehydration and rehydration, according to its hygroscopic nature and to the arrangement of the water molecules in the crystal lattice. Dehydration and rehydration were observed and confirmed by variable temperature X-ray diffraction on the basis of the DSC pattern and TG analysis that shows, by heating the sample from 40 to 200 °C, a loss of 5% weight corresponding to a water molecule loss. The water loss causes a phase transition to a more dense phase that can be rehydrated if it is left in a humid environment. The solid state characterization of NaIb monohydrate has been performed by X-ray single crystal diffraction analysis. The NaIb crystallizes as monohydrate salt in the triclinic system, space group P-1, with Z = 2, a = 5.973(1) Å, b = 9.193(1) Å, c = 14.830(2) Å, α = 98.22(1)°, β = 98.97(1)°, γ = 93.74(1)°, V = 792.9(2) Å3. Each anionic group exist as zwitterionic entity with a total charge of −1. In the crystal packing, the octahedral coordination around the Na cations determines a centrosymmetric double chains structure elongated into the  direction. The water molecules are located inside the inter-chains cavities.
Authors:Mohd Abu Bakar, Zoltan Nagy, and Christopher Rielly
this reason, an extensive characterisation of all known solid forms of the API is necessary in order to understand and differentiate them properly. Solidstatecharacterisation has become an integral part of the drug development process and its