Forced Solid-State Oxidation Studies of Nifedipine-PVP Amorphous Solid Dispersion

Saraf, Isha; Roškar, Robert; Modhave, Dattatray; Brunsteiner, Michael; Karn, Anjali; Neshchadin, Dmytro; Gescheidt, Georg; Paudel, Amrit

doi:10.1021/acs.molpharmaceut.1c00678

Cited by 12 publications

(9 citation statements)

References 53 publications

(74 reference statements)

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“…Given that the computational method is established herein, the future effort in calculating C–H BDE of the ionized state of the molecules can help in making a quick risk-assessment of autoxidation in solution state. Further, the BDE calculations of the H-bonded states of molecules can be relevant to the solid-state autoxidation propensities …”

Section: Discussionmentioning

confidence: 99%

“…The outcome of the present studies set the motivation for the next steps in this direction such as Given that the computational method is established herein, the future effort in calculating C–H BDE of the ionized state of the molecules can help in making a quick risk-assessment of autoxidation in solution state. Further, the BDE calculations of the H-bonded states of molecules can be relevant to the solid-state autoxidation propensities There has been a continual attempt in relating the thermodynamic descriptors to the kinetics (e.g., reaction rates).…”

Section: Discussionmentioning

confidence: 99%

“…Further, the BDE calculations of the H-bonded states of molecules can be relevant to the solid-state autoxidation propensities. 57 2. There has been a continual attempt in relating the thermodynamic descriptors to the kinetics (e.g., reaction rates).…”

Section: Salient Findings and Limitations Of The Study Andmentioning

confidence: 99%

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Theoretical and Experimental Investigation of Autoxidation Propensity of Selected Drugs in Solution State

et al. 2023

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The C−H bond dissociation energy (BDE) of drug molecules is often used to estimate their relative propensities to undergo autoxidation. BDE calculations based on electronic structures provide a convenient means to estimate the risk for a given compound to degrade via autoxidation. This study aimed to verify the utility of calculated C−H BDEs of a range of drug molecules in predicting their autoxidation propensities, in the solution state. For the autoxidation study, 2,2′-azobis (2methylpropionitrile) was employed as the solution state stressor, and the experimental reaction rate constants were determined employing ultraperformance liquid chromatographic (UPLC) methods. Reaction rates in the solution state were compared to the calculated C−H BDE values of the respective compounds. The results indicated a poor correlation for compounds in the solution state, and their relative stabilities could not be explained with C−H BDE. On the other hand, a favorable relationship was observed between the relative extent of ionization and the autoxidation rates of the selected compounds. In the solution state, factors such as the type and extent of drug ionization, degree and type of solvation have been shown to contribute to differences in reactivity. By applying the computational method involving the effect of H-atom abstraction and potential ionization sites in the molecule, the calculated C−H BDE should relate better to the experimental autoxidation rates.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Theoretical and Experimental Investigation of Autoxidation Propensity of Selected Drugs in Solution State

et al. 2023

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“…The interaction between nifedipine molecules and PVP K-30 can occur during the process of making solid dispersions. Nifedipine molecules will be dispersed and trapped in the PVP polymer network, and when heated, the physical state of nifedipine can change into an amorphous form (Kothari et al, 2015;Saraf et al, 2022).…”

Section: Solid Dispersion Sample Preparationmentioning

confidence: 99%

Formulation of Nifedipine–Polyvinyl Pyrrolidone (PVP) Solid Dispersion System and Intrinsic Dissolution Rate Evaluation

2022

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Nifedipine is a drug that acts as an antihypertensive and anti-angina. Nifedipine is known as a drug with poor water solubility. This characteristic will affect the intrinsic dissolution rate so that it can affect the absorption process and reduce the amount of drug that reaches systemic circulation. One of the strategies to increase the intrinsic dissolution rate is developing nifedipine to solid dispersions form. This study aims to observe the intrinsic dissolution rate of nifedipine after it has been made into a solid dispersion. Four samples were prepared, including three solid dispersions of nifedipine-PVP K-30 and one sample of pure nifedipine. The results of the intrinsic dissolution tests are then interpreted through the intrinsic dissolution rate constant (G). The solid dispersions with concentration of nifedipine-PVP K-30 90%:10%; 75%:25%; 60%:40% (w/w), and pure nifedipine produced G values of 3.63; 9.33; 12.63; and 2.08 µg/mm2. min1, consecutively. It shows that the formulation of nifedipine-PVP K-30 solid dispersions has higher G values than pure nifedipine. In addition, increasing PVP K-30 concentration up to 40 % (w/w) can increase the intrinsic dissolution rate of the nifedipine-PVP K-30 solid dispersion system.

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“…33 Several reports have highlighted the unintended degradation of drugs induced via mechanoactivation during ambient or cryogenic dry milling such as that reported for praziquantel, 34 quinapril HCl, 35 gabapentin, 36 and furosemide. 37 Previous experiences from our lab have shown that some drugs (e.g., droperidol 38 and nifedipine 39 ) undergo autoxidation in the presence of polymers containing free radicals. Pas et al have reported in-process degradation of indomethacin due to the generation of free radicals by the polymer during cryo-milling of indomethacin− PVP.…”

Section: Introductionmentioning

confidence: 99%

Mechanoactivation as a Tool to Assess the Autoxidation Propensity of Amorphous Drugs

et al. 2023

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Mechanoactivation has attracted considerable attention in the pharmaceutical sciences due to its ability to generate amorphous materials and solid-state synthetic products without the use of solvent. Although some studies have reported drug degradation during milling, no studies have systematically investigated the use of mechanoactivation in predicting drug degradation in the solid state. Thus, this work explores the autoxidation of drugs in the solid state by comilling amorphous mifepristone (MFP):polyvinylpyrrolidone vinyl acetate (PVPVA) and amorphous olanzapine (OLA):PVPVA. MFP was amorphized by ball milling and OLA by quench cooling techniques. Subsequently, comilling the amorphous drugs in the presence of a 10-fold weight ratio of PVPVA (the excipient containing reactive free radicals) was performed at several milling frequencies to identify the kinetics of mechano-autoxidation over milling durations. Overall, milling led to the degradation of up to 5% drug in the solid state. The autoxidation mechanism was confirmed by performing a stress study in the solution at 50 °C for 5 h, by using a 10 mM azo-bis(isobutyronitrile) (AIBN) as a stressing agent. By deconvoluting the effect of milling frequency and the energy on the extent and kinetics of milling-induced autoxidation of amorphous drugs, it was possible to fit an extended Arrhenius model that allowed extrapolation of mechanoactivated degradation rates (K m) to zero milling frequencies. Further, the autoxidation rates of drugs stored at high temperatures were observed to follow an Arrhenius behavior. A good degree of agreement was observed between the model predictions obtained by mechanoactivation (K m) to the reaction rates observed under accelerated temperatures. Additionally, the impact of adding an antioxidant (e.g., butylated hydroxytoluene) to the mixture during comilling was also examined. This study can be helpful in evaluating the stability of amorphous solids stored in accelerated (non-hermetic) conditions, in screening solid-state autoxidation propensity of drugs, and for the rational selection of antioxidants.

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Forced Solid-State Oxidation Studies of Nifedipine-PVP Amorphous Solid Dispersion

Cited by 12 publications

References 53 publications

Theoretical and Experimental Investigation of Autoxidation Propensity of Selected Drugs in Solution State

Theoretical and Experimental Investigation of Autoxidation Propensity of Selected Drugs in Solution State

Formulation of Nifedipine–Polyvinyl Pyrrolidone (PVP) Solid Dispersion System and Intrinsic Dissolution Rate Evaluation

Mechanoactivation as a Tool to Assess the Autoxidation Propensity of Amorphous Drugs

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