Synthon Approach in Crystal Engineering to Modulate Physicochemical Properties in Organic Salts of Chlorpropamide.

The formulation of drug with improved bioavailability is always challenging and indispensable in the field of pharmaceutics. The control of intermolecular interactions via crystal engineering approach and solid-state molecular recognition results in the formation of active drug molecules with modulated pharmacological benefits. Therefore, with the aim to improve the solubility and dissolution rate of the drug chlorpropamide (CPA), the mechanochemical liquid-assisted grinding (LAG) of the drug with several pharmaceutically accepted excipients was performed. This contributed to the discovery of six novel solid phases, namely salts, salt cocrystals and salt cocrystal hydrate─the salt of CPA with 3, 4-diaminopyridine (DAP); salt and salt cocrystal (SC) polymorph (Z″=3) with 1, 4-diazabicyclo [2.2.2] octane (DABCO); a salt, SC polymorph (Z″=9), and a SC hydrate (Z″=9) with piperazine (PIP). The formation of these salts and salt cocrystals are mainly guided by the strong hydrogen bonds with tunable strength having high electrostatic contribution. This attractive interaction brings the donor and the acceptor atoms close to each other for a facile proton transfer. Furthermore, the conformational constraints on the drug molecules, provided by the excipients via strong and directional hydrogen bonds, are quite impressive as this leads to the identification and characterization of "new conformational isomers" for the CPA molecules. The new crystalline phases exhibit enhanced intrinsic dissolution rate in comparison to that of the pure drug, the magnitude being 7, 131, and 120 folds for CPADAP, CPADABCO_II, and CPAPIP_III, respectively. Furthermore, it is interesting to note that the order of solubility is enhanced by 2.7-, 3-, and 7-fold, respectively, for the abovementioned salts. This also mirrors the trends in the magnitude of the binding energy, the higher magnitude being reflected in the lower solubility. Additionally, the in vivo experiments performed in SD rats results in the enhancement of the magnitude of the pharmacokinetic properties, when compared to the pristine drug. The concentration of the drug in CPADABCO_II and CPAPIP_III formulations exhibits 6- and 4-fold increments, respectively. Indeed, these results corroborate to the trends observed in the structural characterization, intermolecular energy calculations, solubility, and in vitro dissolution assessments.

Understanding Dynamics of Polymorphic Conversion during the Tableting Process Using In Situ Mechanical Raman Spectroscopy.

The objective of this study is to achieve a fundamental understanding of polymorphic interconversion during the tableting process, including during compaction, dwell, decompression/unloading, and ejection using an in situ mechanical Raman spectroscopy. The fit-for-purpose in situ mechanical Raman spectroscopy developed herein can provide simultaneous measurement of Raman spectra and densification for the powder compacts. Chlorpropamide (CPA), an antidiabetic drug, was selected as a model pharmaceutical compound because of its mechanical shear-induced polymorphic conversions. The results confirm that CPA polymorph A (CPA-A) was transformed to CPA polymorph C (CPA-C) under different compaction stresses. We also observed that the converted polymorph CPA-C could be reverted to the CPA-A due to the elastic recovery of powder compacts as detected during dwelling and unloading. This study is the first depiction of the dynamics of CPA polymorphic interconversion during compression, dwell, unloading, and ejection. Mechanistically, this study illustrates a correlation between the change in the powder compact's relative density and polymorphic interconversion of the drug substance in different solid-state forms. The present research suggests that the process-induced polymorph conversion is a complicated dynamic process, which could be affected by the compaction pressure, the elasticity/plasticity of the material, the level of elastic recovery, and the dissipation of residual stress. In summary, this study demonstrates that the in situ mechanical Raman spectroscopy approach enables the simultaneous detection of mechanical and chemical information of the powder compact throughout the tableting process.

Modulated Protein Binding Ability of Anti-Diabetic Drugs in Presence of Monodispersed Gold Nanoparticles and its Inhibitory Potential towards Advanced Glycated End (AGE) Product Formation.

Binding strength of the anti-diabetic drugs chlorpropamide (CPM) and tolbutamide (TBM) with model protein bovine serum albumin (BSA) shows strong modulation in presence of colloidal gold nanoparticles (AuNP). Intrinsic tryptophan fluorescence of both the native BSA and BSA-AuNP conjugate quenched in presence of the drugs. Stern-Volmer quenching constant (KSV) of CPM binding to BSA-AuNP conjugate at different temperatures is almost twice (6.76~14.76 × 103 M-1) than the corresponding values in native BSA (3.21~5.72 × 103 M-1). However, the calculated KSV values with TBM show certain degree of reduction in presence of AuNP (6.46× 103 M-1), while comparing with native BSA (8.83 × 103 M-1). The binding mode of CPM towards BSA-AuNP conjugate is mainly through hydrophobic forces; whereas, TBM binding is identified to be Van der Waal's and hydrogen bonding type of interaction. Fluorescence lifetime analysis confirms static type of quenching for the intrinsic tryptophan fluorescence of BSA as well as BSA-AuNP conjugate with addition of CPM and TBM at different concentrations. The α-helical content in the secondary structure of BSA is decreased to 48.32% and 45. 28% in presence of AuNP, when the concentration of CPM is 0.08 mM and 0.16 mM in comparison with that of native protein (50.13%). On the other hand, the intensity of sugar induced advanced glycated end (AGE) product fluorescence is decreased by 55% and 80% at 0.13 nM and 0.68 nM AuNP, respectively. Change in the binding strength of the drugs with transport protein and reduced AGE product formation in presence of AuNP could lead to a major development in the field of nanomedicine and associated drug delivery techniques. Graphical Abstract Modulated drug binding ability and AGE product formation of serum proteins in presence of AuNP.

Interaction of chlorpropamide with serum albumin: Effect on advanced glycated end (AGE) product fluorescence.

Carrier proteins like bovine or human serum albumin (BSA and HSA, respectively) are prone to glycation as compared to the other available proteins. In this study, reducing sugars such as l-arabinose (ara), d-(-) galactose (gal) and d-(-) fructose (fru) were used to create model glycated serum albumins and binding ability of these with well-known antidiabetic drug chlorpropamide (CPM) was monitored. Fluorescence quenching experiment revealed that interaction of CPM with native as well as glycated albumins undergoes through a ground state complex formation. CPM binds strongly to glycated HSA with arabinose (gHSAara) as compared to other glycated systems and to the native proteins. CPM interacts through Van der Waals and hydrogen bonding interaction to glycated BSA by d-(-) fructose (gBSAfru) and also with native HSA; whereas, it's interaction with BSA and others glycated systems like gBSAara, gBSAgal and gHSAara occurs primarily through hydrophobic interaction. CPM showed an enhancement in the production of the advanced glycated end products (AGE) in all the glycated proteins. The difference in the binding capability of CPM to differently glycated albumins could be a major model to understand the drug carrying capacity of the glycated serum albumins.

Compression-Induced Polymorphic Transformation in Tablets: Role of Shear Stress and Development of Mitigation Strategies.

Our goals were to evaluate the effects of (i) hydrostatic pressure alone and (ii) its combined effect with shear stress during compaction, on the polymorphic transformation (form C → A) of a model drug, chlorpropamide. The powder was either subjected to hydrostatic pressure in a pressure vessel or compressed in a tablet press, at pressures ranging from 25 to 150 MPa. The overall extent of phase transformation was determined by powder X-ray diffractometry, whereas 2D-X-ray diffractometry enabled quantification of the spatial distribution of phase composition in tablets. Irrespective of the pressure, the extent of transformation following compaction was higher than that because of hydrostatic pressure alone, the difference attributed to the contribution of shear stress experienced during compaction. At a compression pressure of 25 MPa, there was a pronounced gradient in the extent of phase transformation when monitored from radial tablet surface to core. This gradient decreased with increase in compression pressure. Four approaches were attempted to minimize the effect of compression-induced phase transformation: (a) site-specific lubrication, (b) use of a viscoelastic excipient, (c) ceramic-lined die, and (d) use of cavity tablet. The ceramic-lined die coupled with site-specific lubrication was most effective in minimizing the extent of compression-induced phase transformation.

Chromatographic studies of chlorpropamide interactions with normal and glycated human serum albumin based on affinity microcolumns.

Sulfonylurea drugs have significant binding to proteins in blood, with most of this binding believed to occur with human serum albumin (HSA). High performance affinity chromatography and affinity microcolumns containing immobilized HSA were used to investigate binding by the sulfonylurea drug chlorpropamide to normal HSA and glycated HSA, which is a modified form of HSA that has an increased serum concentration in diabetes. Experiments employing frontal analysis indicated that the binding by chlorpropamide gave a good fit to a two-site model for both normal HSA and glycated HSA samples that were representative of controlled or advanced diabetes. These interactions involved a set of moderate-to-high affinity sites and a set of lower affinity sites, with binding constants in the range of 6.2-9.9 × 104 M-1 and 0.18-0.57 × 104 M-1, respectively, at pH 7.4 and 37 °C. Competition studies utilizing a zonal elution format demonstrated that chlorpropamide could interact at both Sudlow sites I and II of HSA, with affinities in the range expected for the moderate-to-high affinity sites of this drug. The affinity of chlorpropamide at Sudlow site I had a small increase of up to 1.2-fold when comparing the normal HSA and glycated HSA samples. Chlorpropamide gave a larger 1.4- to over 1.5-fold increase at Sudlow site II when the affinity of this drug was compared between normal HSA and the same samples of glycated HSA. These results were compared to those obtained previously with other sulfonylurea drugs to help determine how glycation can change the overall and site-selective binding strength of these drugs with HSA at levels of protein modification that are seen in patients with diabetes.

Quantitative determination of carfilzomib in mouse plasma by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study.

A highly sensitive and rapid LC-MS/MS method was developed and validated to determine the levels of carfilzomib in mice plasma by using chlorpropamide as an internal standard. Carfilzomib and chlorpropamide were extracted from 5 µL of plasma after protein precipitation with acetonitrile. Chromatographic separation was performed on Phenomenex Luna C18 column (50×2.0mm id, 3µm). The mobile phase consisted of 0.1% formic acid in acetonitrile -0.1% formic acid in water (1:1v/v) and the flow rate was 0.3mL/min. The total chromatographic run time was 2.5min. Detection was performed on a triple quadrupole mass spectrometer equipped with positive-ion electrospray ionization by selected reaction monitoring of the transitions at m/z 720.20>100.15 (for carfilzomib) and m/z 277.05>111.05 (for the internal standard). The lower limit of quantification was 0.075ng/mL and the linear range was 0.075-1250ng/mL (r≥0.9974). All validation data, including selectivity, precision, accuracy, matrix effect, recovery, dilution integrity, stability, and incurred sample reanalysis, were well within acceptance limits. This newly developed bioanalytical method was simple, highly sensitive, required only a small volume of plasma, and was suitable for application in pharmacokinetic studies in mice that used serial blood sampling.

Quantification and modeling of nanomechanical properties of chlorpropamide α, ß, and γ conformational polymorphs.

The nanomechanical properties of the α-, ß-, and γ- conformational polymorphs of chlorpropamide were determined by the dynamic contact module continuous stiffness measurement at nanoindenter. The mechanical anisotropy of the α-polymorph was confirmed by indenting different faces, and its deformational behavior was assigned as ductile. Based on the nanoindentation results, the ß and γ forms are moderately hard with plastic flow at contact points. The results revealed a correlation between Young's modulus and inter-planar interaction energy with regard to crystal orientation. Interpretation of the measurements was assisted by two- and three-dimensional periodic density functional theory (DFT) calculations, yielding inter-planar energies of polymorphs along the cell vectors and exhibiting a very good match with the experimental observations. The results suggest that the inter-planar interaction energy could serve as a first-order indicator for ranking the mechanical propensity of crystalline active ingredients. The study confirms the practical aspect of using the α- form for preparing chlorpropamide tablets with a direct compression procedure due to its substantial level of ductility.

The polymorphic phase transformations in the chlorpropamide under pressure.

The crystal structure and vibrational spectra of the chlorpropamide have been studied by means of the X-ray diffraction and Raman spectroscopy at pressures up to 24.6 and 4.4 GPa, respectively. Two polymorphic phase transitions, between initial orthorhombic form-A and a monoclinic form-AI at P ∼ 1.2 GPa and, in additional, to another monoclinic form-AII at P ∼ 3.0 GPa, were observed. At pressures above 9.6 GPa, a transformation to the amorphous phase of chlorpropamide was revealed. The lattice parameters, unit cell volumes, and vibration modes as functions of pressure were obtained for the different polymorphic modifications of chlorpropamide.

A novel method for determining the solubility of small molecules in aqueous media and polymer solvent systems using solution calorimetry.

PURPOSE: To explore the application of solution calorimetry for measuring drug solubility in experimentally challenging situations while providing additional information on the physical properties of the solute material. METHODS: A semi-adiabatic solution calorimeter was used to measure the heat of dissolution of prednisolone and chlorpropamide in aqueous solvents and of griseofulvin and ritonavir in viscous solutions containing polyvinylpyrrolidone and N-ethylpyrrolidone. RESULTS: Dissolution end point was clearly ascertained when heat generation stopped. The heat of solution was a linear function of dissolved mass for all drugs (<10% RSD, except for chlorpropamide). Heats of solution of 9.8 ± 0.8, 28.8 ± 0.6, 45.7 ± 1.6 and 159.8 ± 20.1 J/g were obtained for griseofulvin, ritonavir, prednisolone and chlorpropamide, respectively. Saturation was identifiable by a plateau in the heat signal and the crossing of the two linear segments corresponds to the solubility limit. The solubilities of prednisolone and chlopropamide in water by the calorimetric method were 0.23 and 0.158 mg/mL, respectively, in agreement with the shake-flask/HPLC-UV determined values of 0.212 ± 0.013 and 0.169 ± 0.015 mg/mL, respectively. For the higher solubility and high viscosity systems of griseofulvin and ritonavir in NEP/PVP mixtures, respectively, solubility values of 65 and 594 mg/g, respectively, were obtained. CONCLUSION: Solution calorimetry offers a reliable method for measuring drug solubility in organic and aqueous solvents. The approach is complementary to the traditional shake-flask method, providing information on the solid properties of the solute. For highly viscous solutions, the calorimetric approach is advantageous.

A high-pressure polymorph of chlorpropamide formed on hydrostatic compression of the α-form in saturated ethanol solution.

The crystal structure of the high-pressure polymorph (α') of an antidiabetic drug, chlorpropamide [4-chloro-N-(propylaminocarbonyl)benzenesulfonamide, C(10)H(13)ClN(2)O(3)S], which is formed at ~2.8 GPa from the α-polymorph (P2(1)2(1)2(1)) on hydrostatic compression in saturated ethanol solution, has been determined. As a result of the phase transition, the a, c and α parameters change jumpwise, whereas the changes in b parameter are continuous through the phase transition point. The high-pressure form is monoclinic (P2(1)11) and has Z' equal to 2, the two independent molecules differing in their conformations. The hydrogen bonds expand slightly in the high-pressure polymorph after the transition, and this expansion is interrelated with the changes in molecular conformations enabling a denser packing. The transition is reversible, but the crystal quality deteriorates as a result of multiple compression-decompression cycles, and a pseudomerohedral twinning accompanies the transformation.

Solid-state transformations in the ß-form of chlorpropamide on cooling to 100 K.

A single-crystal X-ray diffraction study of the effect of cooling down to 100 K on the ß-form of chlorpropamide, 4-chloro-N-(propylaminocarbonyl)benzenesulfonamide, has revealed reversible phase transitions at ∼257 K and between 150 and 125 K: ß (Pbcn, Z' = 1) ⇔ ß(II) (P2/c, Z' = 2) ⇔ ß(III) (P2/n, a' = 2a, Z' = 4); the sequence corresponds to cooling. Despite changes in the space group and number of symmetry-independent molecules, the volume per molecule changes continuously in the temperature range 100-300 K. The phase transition at ∼257 K is accompanied by non-merohedral twinning, which is preserved on further cooling and through the second phase transition, but the original single crystal does not crack. DSC (differential scanning calorimetry) and X-ray powder diffraction investigations confirm the phase transitions. Twinning disappears on heating as the reverse transformations take place. The second phase transition is related to a change in conformation of the alkyl tail from trans to gauche in 1/4 of the molecules, regularly distributed in the space. Possible reasons for the increase in Z' upon cooling are discussed in comparison to other reported examples of processes (crystallization, phase transitions) in which organic crystals with Z' > 1 have been formed. Implications for pharmaceutical applications are discussed.

Evaluation and modeling of the eutectic composition of various drug-polyethylene glycol solid dispersions.

The purpose of this study was to gain a better understanding of which factors contribute to the eutectic composition of drug-polyethylene glycol (PEG) blends and to compare experimental values with predictions from the semi-empirical model developed by Lacoulonche et al. Eutectic compositions of various drug-PEG 3350 solid dispersions were predicted, assuming athermal mixing, and compared to experimentally determined eutectic points. The presence or absence of specific interactions between the drug and PEG 3350 were investigated using Fourier transform infrared (FT-IR) spectroscopy. The eutectic composition for haloperidol-PEG and loratadine-PEG solid dispersions was accurately predicted using the model, while predictions for aceclofenac-PEG and chlorpropamide-PEG were very different from those experimentally observed. Deviations in the model prediction from ideal behavior for the systems evaluated were confirmed to be due to the presence of specific interactions between the drug and polymer, as demonstrated by IR spectroscopy. Detailed analysis showed that the eutectic composition prediction from the model is interdependent on the crystal lattice energy of the drug compound (evaluated from the melting temperature and the heat of fusion) as well as the nature of the drug-polymer interactions. In conclusion, for compounds with melting points less than 200°C, the model is ideally suited for predicting the eutectic composition of systems where there is an absence of drug-polymer interactions.

Small scale screening to determine the ability of different polymers to inhibit drug crystallization upon rapid solvent evaporation.

In this study, the ability of 7 chemically diverse polymers [Eudragit E100 (E100), poly(acrylic acid) (PAA), poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-vinyl acetate) (PVPVA), poly(styrene sulfonic acid) (PSSA), hydroxypropylmethylcellulose (HPMC) and hydroxypropylmethylcellulose acetate succinate (HPMCAS)] to inhibit the crystallization of 8 readily crystallizable model compounds [benzamide (BD), phenacetin (PH), flurbiprofen (FB), flufenamic acid (FFA), chlorpropamide (CP), chlorzoxazone (CZ), bifonazole (BI) and lidocaine (LI)] was investigated. Films of the different drug-polymer combinations were prepared by rapid evaporation from solution, using a spin coating method. A total of 7 different drug/polymer weight ratios [90/10, 75/25, 60/40, 50/50, 40/60, 25/75 and 10/90 (w/w)] were evaluated for each drug-polymer combination. Crystallization behavior of the films was monitored using polarized light microscopy over 7 days of room temperature storage under dry conditions. It was observed that compounds having a higher crystallization tendency for the pure compound tended to be more difficult to stabilize using the polymeric additives; more polymer was required. In addition, the stabilizing ability of the polymers varied considerably for the individual compounds, with the acidic polymers PAA and PSSA showing the most extreme behavior. The acidic polymers were good stabilizers for the drugs with basic and amide functional groups, but extremely poor stabilizers for acidic drugs. A reasonable correlation between crystallization inhibition in spin coated films versus bulk powders (prepared by rotary evaporation) was observed. The small scale screening method is thus a potentially useful technique to evaluate the role of drug-polymer chemistry in the stabilization of amorphous solid dispersions.

Evaluation of the microstructure of semicrystalline solid dispersions.

As a result of an increase in the number of emerging therapies with dissolution limited bioavailability, formulation strategies such as solid dispersions that enhance the rate of solubilization are of interest. In this study, the microstructure of solid dispersions prepared with polyethylene glycol (PEG) and four model compounds with different physicochemical properties was evaluated using a variety of experimental techniques. Solid dispersions were prepared by fusion and evaluated using small-angle X-ray scattering (SAXS), powder X-ray diffraction (PXRD), atomic force microscopy (AFM), optical microscopy and differential scanning calorimetry (DSC). SAXS results indicated that aceclofenac and chlorpropamide solid dispersions favored the interlamellar incorporation of the drug in the PEG matrix. Optical microscopy did not show any evidence of interspherulitic accumulation for any of the model compounds. Haloperidol was highly crystalline in the dispersions, whereas evidence of amorphous material was found for the other model compounds. Results indicated that both the crystallization tendency of the drug and its solubility in amorphous regions of PEG played important roles in determining the location (i.e., interlamellar, interfibrillar or interspherulitic regions) and size of the drug domains within the dispersion.

Selective detection and quantitation of organic molecule crystallization by second harmonic generation microscopy.

Second order nonlinear optical imaging of chiral crystals (SONICC) was applied to selectively detect crystal formation at early stages and characterize the kinetics of nucleation and growth. SONICC relies on second harmonic generation (SHG), a nonlinear optical effect that only arises from noncentosymmetric ordered domain structures, which include crystals of chiral molecules. The model systems studied include pharmaceutically relevant compounds: griseofulvin and chlorpropamide. SONICC demonstrates low detection limits producing an 8 order of magnitude improvement relative to macroscopic average techniques and 5 order of magnitude improvement relative to optical microscopy. SONICC was also applied to examine the kinetics of crystallization in amorphous griseofulvin. The results show that SONICC enables simultaneous monitoring of individual crystal growth, nucleation rate, and macroscopic crystallization kinetics.

Crystallization and polymorphic transitions of chlorpropamide in aqueous 2-hydroxybutyl-beta-cyclodextrin solution.

Effects of cyclodextrins on crystallization of chlorpropamide and the polymorphic transition mechanism of the drug in aqueous solution were investigated. In the presence of 2-hydroxybutyl-beta-cyclodextrin, chlorpropamide was exclusively crystallized to metastable Form II and III polymorphs, whereas it was crystallized to stable Form A in the absence of the beta-cyclodextrin at 4 degrees C. The crystallization to metastable Form II or III polymorph was dependent upon 2-hydroxybutyl-beta-cyclodextrin concentrations employed, i.e. crystallization to Form III at a lower concentration (0.5 mM), whereas to Form II in a higher concentration (5 mM). At an intermediate concentration (2 mM), the least stable Form II crystal was initially precipitated, but it was transformed to Form III crystal. At higher temperature, Form III crystal was converted to stable Form A crystal. In aqueous solution, chlorpropamide crystallized to stable Form A crystal consecutively through metastable Forms II and III, according to "Ostwald's Rule of Stages". 2-Hydroxybutyl-beta-cyclodextrin inhibits the transition of Form II to Form III at higher concentrations and that of Form III to Form A at lower concentrations. The results suggest that 2-hydroxybutyl-beta-cyclodextrin is useful for selective preparation of metastable chlorpropamide polymorphs occurring during crystallization according to the Ostwald's rule.

A conformational polymorphic transition in the high-temperature epsilon-form of chlorpropamide on cooling: a new epsilon'-form.

Structural changes in the high-temperature -polymorph of chlorpropamide, 4-chloro-N-(propylaminocarbonyl)benzenesulfonamide, C(10)H(13)ClN(2)O(3)S, on cooling down to 100 K and on reverse heating were followed by single-crystal X-ray diffraction. At temperatures below 200 K the phase transition into a new polymorph (termed the epsilon'-form) has been observed for the first time. The polymorphic transition preserves the space group Pna2(1), is reversible and is accompanied by discontinuous changes in the cell volume and parameters, resulting from changes in molecular conformation. As shown by IR spectroscopy and X-ray powder diffraction, the phase transition in a powder sample is inhomogeneous throughout the bulk, and the two phases co-exist in a wide temperature range. The cell parameters and the molecular conformation in the new polymorph are close to those in the previously known alpha-polymorph, but the packing of the z-shaped molecular ribbons linked by hydrogen bonds inherits that of the epsilon-form and is different from the packing in the alpha-polymorph. A structural study of the alpha-polymorph in the same temperature range has revealed no phase transitions.

Quantitative 35Cl nuclear quadrupole resonance in tablets of the antidiabetic medicine Diabinese.

Pulsed (35)Cl nuclear quadrupole resonance (NQR) experiments have been performed on 250-mg tablets of the antidiabetic medicine Diabinese to establish the conditions needed for noninvasive quantitative analysis of the medicine in standard bottles. One important condition is the generation of a uniform radio-frequency (RF) field over the sample, which has been achieved by two designs of sample coil: one of variable pitch, and the other a resonator that has been fabricated from a single turn of copper sheet with a longitudinal gap bridged by tuning capacitors. The results from blind tests show that the number of tablets in a bottle could be predicted to within +/-3%.

NMR search for polymorphic phase transformations in chlorpropamide form-A at high pressures.

The high-pressure effects on chlorpropamide (C10H13ClN2O3S) form-A have been studied by 1H NMR spectroscopy at high pressures up to 800 MPa in the temperature range 90-300 K. A study of the NMR second moment and spin-lattice relaxation time has been completed by a calculation of the steric hindrances for molecular reorientations and simulations of the second moment of the NMR line by the Monte-Carlo method, which enabled a precise description of molecular dynamics in the compound studied. Reorientations of the methyl group, oscillations and reorientations of the chlorophenyl ring and reorientations of the propyl group have been revealed and respective activation parameters extracted. No phase transformation of the compound form-A has been detected.