Chemometrics-assisted study of the interconversion between the crystalline forms of nimodipine

Calvo, Natalia Lorena; Balzaretti, Naira Maria; Antonio, Marina; Kaufman, Teodoro S.; Maggio, Rubén M.

doi:10.1016/j.jpba.2018.06.019

Cited by 9 publications

(4 citation statements)

References 31 publications

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“…A study conducted by Calvo et al reported this peak as the fingerprint region for differentiation between two modifications of NMD. Based on their report, this peak was only observed in mod I of NMD and was absent in the IR spectrum of mod II . The existence of this peak in NMD powder and its change in the NMD 40% sample can be due to possible changes in modifications of NMD during the extrusion process, which was also observed by DSC.…”

Section: Resultsmentioning

confidence: 76%

Characterization of Controlled Release Starch-Nimodipine Implant for Antispasmodic and Neuroprotective Therapies in the Brain

Esfahani,

Trutschel,

Reichert

et al. 2023

Mol. Pharmaceutics

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Parenteral depot systems can provide a constant release of drugs over a few days to months. Most of the parenteral depot products on the market are based on poly(lactic acid) and poly(lactide-co-glycolide) (PLGA). Studies have shown that acidic monomers of these polymers can lead to nonlinear release profiles or even drug inactivation before release. Therefore, finding alternatives for these polymers is of great importance. Our previous study showed the potential of starch as a natural and biodegradable polymer to form a controlled release system. Subarachnoid hemorrhage (SAH) is a life-threatening type of stroke and a major cause of death and disability in patients. Nimotop® (nimodipine (NMD)) is an FDA-approved drug for treating SAH-induced vasospasms. In addition, NMD has, in contrast to other Ca antagonists, unique neuroprotective effects. The oral administration of NMD is linked to variable absorption and systemic side effects. Therefore, the development of a local parenteral depot formulation is desirable. To avoid the formation of an acidic microenvironment and autocatalytic polymer degradation, we avoided PLGA as a matrix and investigated starch as an alternative. Implants with drug loads of 20 and 40% NMD were prepared by hot melt extrusion (HME) and sterilized with an electron beam. The effects of HME and electron beam on NMD and starch were evaluated with NMR, IR, and Raman spectroscopy. The release profile of NMD from the systems was assessed by high-performance liquid chromatography. Different spectroscopy methods confirmed the stability of NMD during the sterilization process. The homogeneity of the produced system was proven by Raman spectroscopy and scanning electron microscopy images. In vitro release studies demonstrated the sustained release of NMD over more than 3 months from both NMD systems. In summary, homogeneous nimodipine-starch implants were produced and characterized, which can be used for therapeutic purposes in the brain.

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Section: Resultsmentioning

confidence: 76%

Characterization of Controlled Release Starch-Nimodipine Implant for Antispasmodic and Neuroprotective Therapies in the Brain

Esfahani,

Trutschel,

Reichert

et al. 2023

Mol. Pharmaceutics

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“…Nim is divided into the H and L crystal forms, depending on the melting point, with bioequivalence. 55 It is noted that there are also two endothermic peaks in the products. The second endothermic peak is at 353.65 K, which is further lower than the melting points of Nim (190.50 and 400.18 K).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…There are two heat absorption peaks in Nim corresponding to his two crystal forms. Nim is divided into the H and L crystal forms, depending on the melting point, with bioequivalence . It is noted that there are also two endothermic peaks in the products.…”

Section: Resultsmentioning

confidence: 99%

Design of Single and Multicomponent Drug Spherical Particles with Improved Powder Properties in Water Instead of Organic Solvents: A Case Study of Gemfibrozil

Wang

Liu

Guo

et al. 2022

ACS Sustainable Chem. Eng.

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Granulation is an important method to increase the fluidity of compounds, especially drugs with needle-like shapes. Another function of granulation is to mix active pharmaceutical ingredients (APIs) and excipients. In this research, oiling-out spherical agglomeration technology was used to obtain single- and multicomponent drug spherical particles of gemfibrozil, which can be directly compressed. This technology is carried out by simply heating and quenching operations in nonorganic solvents. Compared with the current granulation technology, it is estimated that approximately 400 metric tons (MT) of organic solvents per year can be saved for every 100 MT of gemfibrozil production. Meanwhile, based on the binary oiling-out phase diagram, the spherical particles of gemfibrozil were prepared with high bulk density (0.71 g cm–3), good sphericity (>80%), high yield (>95%), and adjustable particle size distribution, and the flowability is improved by 47.37%. Furthermore, the multicomponent functional particles of gemfibrozil and nimodipine for drug combination with the good morphology and uniform distribution of components were obtained by establishing ternary oiling-out phase diagrams. The results of tablet compaction showed a 4 times increase in tabletability from single-component spherical particles and a 2.7 times increase from multicomponent spherical particles compared to commercial powders. On the other hand, the failing case of gemfibrozil and simvastatin indicated that the binding energy between molecules is the key point of this method, and this result revealed the limitation of the oiling-out spherical agglomeration method for the current selection strategy of drugs. This work provided an experimental and theoretical basis for the further application of this green technology.

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“…Such transformation was unveiled analyzing MIR data by multivariate curve resolution with alternating least squares (MCR-ALS) algorithm, since it has no resolution using thermal analysis (DSC or DTG) [20]. In the same way, the inter-conversion of two crystalline forms of nimodipine was resolved by MCR-ALS and MIR spectroscopy [21]. However, the last approaches were only applied to drug substance and not to formulated products.…”

Section: A C C E P T E Dmentioning

confidence: 99%

Chemometric study of the excipients’ influence on polymorphic-behavior. Mefenamic acid as case of study

Antonio

Calvo

Maggio

2019

Journal of Pharmaceutical and Biomedical Analysis

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The assessment of polymorphism is a problematical issue for regulatory agencies, because variations among crystalline forms of active pharmaceutical ingredient (API) can lead to changes in the efficacy and safety of formulated product. Such conversions are very hard to be detected, thus, the development of techniques for the identification, characterization and quantification of polymorphs results essential in all stages of the manufacturing process. The presence of excipients in formulated products may change the crystal stability of an API, by catalyzing a polymorphic transformation or stabilizing the less stable form. As paradox, all suitable analytical techniques (spectroscopies, thermal analysis, NMR and DRX, and others) for polymorphic analysis are affected by excipients. A deep understanding of the polymorphism-excipient relationship is in full accordance with Quality by Design (QbD) paradigm, the systematic approach focused in quality building into a product based in the full understanding of the products and process. In this work, a novel approach based on thermal stress, MIR monitoring, multivariate curve resolution with alternating least squares (MCR-ALS) and kinetic analysis was developed and applied to monitor polymorphism behavior of model API in formulated products. Commercial tablets, physical mixtures and commercial API, were processed and analyzed under the proposed approach. Commercial tablets of MFA revealed a fast conversion to Form II, contrasting to the behavior of the pure API. Physical mixtures showed similar behavior to commercial tablets, thus reduction in transformation times was related to MFA-excipients physical interaction, even at surface level. Calorimetric studies support the conclusion obtained. The developed approach could be extended to others APIs and other stress sources (humidity, solvents, mechanical forces and its combinations), being a valuable tool for QbD environment.

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Chemometrics-assisted study of the interconversion between the crystalline forms of nimodipine

Cited by 9 publications

References 31 publications

Characterization of Controlled Release Starch-Nimodipine Implant for Antispasmodic and Neuroprotective Therapies in the Brain

Characterization of Controlled Release Starch-Nimodipine Implant for Antispasmodic and Neuroprotective Therapies in the Brain

Design of Single and Multicomponent Drug Spherical Particles with Improved Powder Properties in Water Instead of Organic Solvents: A Case Study of Gemfibrozil

Chemometric study of the excipients’ influence on polymorphic-behavior. Mefenamic acid as case of study

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