Preparation and Transformation of True Nifedipine Polymorphs: Investigated with Differential Scanning Calorimetry and X-Ray Diffraction Pattern Fitting Methods

Grooff, D.; Liebenberg, Wilna; Villiers, Melgardt M. de

doi:10.1002/jps.22419

Cited by 22 publications

(15 citation statements)

References 18 publications

(24 reference statements)

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“…Amorphous pure NIF showed crystallization before one month of storage and the intensity of the peaks grew with time (see Figure 4 c). Partially recrystallized NIF showed characteristic peaks at 9.5

, 11.0

, 17.1

, 24.5

and 26.7

for 2

, indicating recrystallization into polymorph C, which is in accordance to the results reported by Grooff et al [ 31 ]. The PXRD pattern for recrystallized NIF sample after one year presented also weak peaks corresponding to the polymorph A.…”

Section: Resultssupporting

confidence: 91%

Co-Amorphous Simvastatin-Nifedipine with Enhanced Solubility for Possible Use in Combination Therapy of Hypertension and Hypercholesterolemia

2018

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The high index of simultaneous incidence of hypertension and hypercholesterolemia in the population of many countries demands the preparation of more efficient drugs. Therefore, there is a significant area of opportunity to provide as many alternatives as possible to treat these illnesses. Taking advantage of the solubility enhancement that can be achieved when an active pharmaceutical ingredient (API) is obtained and stabilized in its amorphous state, in the present work, new drug-drug co-amorphous formulations (Simvastatin SIM- Nifedipine NIF) with enhanced solubility and stability were prepared and characterized. Results show that the co-amorphous system (molar ratio 1:1) is more soluble than the pure commercial APIs studied separately. Aqueous dissolution profiles showed increments of solubility of 3.7 and 1.7 times for SIM and NIF, correspondingly, in the co-amorphous system. The new co-amorphous formulations, monitored in time, (molar fractions 0.3, 0.5 and 0.7 of SIM) remained stable in the amorphous state for more than one year when stored at room temperature and did not show any signs of crystallization when re-heating. Inspection on the remainder of a sample after six hours of dissolution showed no recrystallization, confirming the stability of co-amorphous system. The enhanced solubility of the co-amorphous formulations makes them promising for simultaneously targeting of hypertension and hypercholesterolemia through combination therapy.

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, 11.0

, 17.1

, 24.5

and 26.7

for 2

Section: Resultssupporting

confidence: 91%

Co-Amorphous Simvastatin-Nifedipine with Enhanced Solubility for Possible Use in Combination Therapy of Hypertension and Hypercholesterolemia

2018

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“…am-NIF showed a T g at 45°C followed by exothermic crystallization to a metastable form at 96°C, which was then exothermically transformed to α-NIF at 119°C followed by melting at 170°C. This corresponds to the values reported by Grooff et al (25,32). The T g of Soluplus® was observed at 76°C.…”

Section: Dscsupporting

confidence: 87%

“…The physical forms of commercially available α-NIF, prepared β-NIF, and prepared am-NIF were confirmed by XRD and Raman spectroscopy (25,31). The chemical stability of nifedipine in am-NIF, and solid dispersion samples prepared by FD, ME and SE was proved and the remaining nifedipine content was between 90.0 and 110.0%.…”

Section: Resultsmentioning

confidence: 99%

“…am-NIF for thermal analysis was formed in situ in the DSC pan by heating α-NIF to 178°C with a heating rate of 10°C/min, holding at 178°C for 15 min and cooling to 0°C with a cooling rate of 50°C/min. β-NIF for thermal analysis was also formed in situ in the DSC pan by a modified method of Grooff et al (25); am-NIF was heated to 120°C at a heating rate of 10°C/min followed immediately by quenching to 0°C. The thermal transitions of am-NIF, β-NIF and α-NIF were measured from 0 to 200°C with a heating rate of 10°C/min.…”

Section: Differential Scanning Calorimetry (Dsc)mentioning

confidence: 99%

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An Investigation of Nifedipine Miscibility in Solid Dispersions Using Raman Spectroscopy

et al. 2015

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“…This sensitivity may explain the variability in published data on the inhibition effect of nifedipine, taking into account that account that researchers used different amounts of ethanol in their samples. Another source of observed difference could be the polymorphism of nifedipine , since there is a significant difference in aqueous solubility of various crystalline forms of nifedipine ranging (at 300 K) from 35 mg/l (for the amorphous form) to 3 mg/l (for the dehydrated form) . These circumstances also apply to this study.…”

mentioning

confidence: 83%

Proposed Dynamics of CDB3 Activation in Human Erythrocytes by Nifedipine Studied with Scanning Flow Cytometry

et al. 2019

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Nifedipine is calcium channels and pumps blocker widely used in medicine. However, mechanisms of nifedipine action in blood are not clear. In particular, the influence of nifedipine on erythrocytes is far from completely understood. In this work, applying scanning flow cytometry, we observed experimentally for the first time the dynamics behind a significant increase of HCO 3 − /Cl − transmembrane exchange rate of CDB3 (main anion exchanger, AE1, Band 3, SLC4A1) of human erythrocytes in the presence of nifedipine in blood. It was found that the rate of CDB3 activation is not limited by the rate of nifedipine binding and/or Ca 2+ transport. In order to explain the experimental data, we suggested a kinetic model assuming that the rate of CDB3 activation is limited by the dynamics of the balance between two intracellular processes (1) the activation of CDB3 limited by its interaction with intracellular Ca 2+ , and (2) the spontaneous deactivation of CDB3. Thus the use of scanning flow cytometry allowed to clarify quantitatively the molecular kinetic mechanism of nifedipine action on human erythrocytes. In particular, the efficiency (~30) and rates of activation (~0.3 min −1 ) and deactivation (~10 −3 min −1 ) of CDB3 in human erythrocytes was evaluated for two donors.Nifedipine is widely used in medicine under the name of Adalat and other drugs. One common usage is the treatment of cardiovascular pathology such as atherosclerosis, coronary heart disease, hypertension, cerebral ischemia, and others (1). Other uses include painful spasms of the esophagus (2,3), Raynaud's phenomenon (4), tocolytic therapy (5). However, the effect of the treatment by nifedipine is not always positive (6). In particular, it is not clear (7) the influence of nifedipine on the rate of HCO 3− /Cl − transmembrane CDB3 protein (AE1, Band 3), which plays an important role in bicarbonate metabolism (8). Overall, a more complete understanding of nifedipine action in blood is needed.Nifedipine belongs to the subclass of dihydropyridines (DHPs), which are known as inhibitors of Ca 2+ transport across the erythrocyte membrane in both pathways: (1) inward leak through Ca 2+ entry channels (9-11), and (2) extrusion by plasma membrane Ca 2+ pumps (PMCA) (12,13). It was reported (13) that about 50% inhibition of PMCA was obtained at extracellular nifedipine concentration of 300 μM. Interestingly, the same extracellular concentration of 300 μM nifedipine was reported (14) to cause less (about 30%) inhibition of Ca 2+ entry channels of erythrocyte membrane. Stronger inhibition of PMCA than entry channels leads to the accumulation of intracellular Ca 2+ in erythrocytes in the presence of extracellular

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Preparation and Transformation of True Nifedipine Polymorphs: Investigated with Differential Scanning Calorimetry and X-Ray Diffraction Pattern Fitting Methods

Cited by 22 publications

References 18 publications

Co-Amorphous Simvastatin-Nifedipine with Enhanced Solubility for Possible Use in Combination Therapy of Hypertension and Hypercholesterolemia

Co-Amorphous Simvastatin-Nifedipine with Enhanced Solubility for Possible Use in Combination Therapy of Hypertension and Hypercholesterolemia

An Investigation of Nifedipine Miscibility in Solid Dispersions Using Raman Spectroscopy

Proposed Dynamics of CDB3 Activation in Human Erythrocytes by Nifedipine Studied with Scanning Flow Cytometry

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