Salt disproportionation: A material science perspective

Thakral, Naveen K.; Kelly, Ron C.

doi:10.1016/j.ijpharm.2017.02.001

Cited by 40 publications

(55 citation statements)

References 63 publications

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“…The study found that there is a reduction in the onset melting temperature of both samples with slower heating rates due to HCl and HBr salt disproportionation. This work supports that HCl salt disproportionation from pilocarpine contributes to melting point depression at slower heating rates (Thakral and Kelly, 2017). The results concluded from the application of stage #4 illustrated the importance of testing the chemical stability of the sample post DSC cycle for a valid melting point measurement.…”

Section: Discussionsupporting

confidence: 71%

“…During the production of a solid dosage form, an API is usually subjected to harsh processing conditions such as wet granulation, drying, roller compaction, and compression (Thakral and Kelly, 2017). Due to these processing requirements, an API salt may disproportionate, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…The trapped HCl will generate a higher concentration of degradation products, thus lowering the pilocarpine HCl recovery, see figure 8. A study conducted by Thakar 2017, tested the salt disproportionation in corticotropin-releasing hormone receptor 1 (CRH-1 HCl and CRH-1 HBr) using different heating rates by DSC (Thakral and Kelly, 2017). The study found that there is a reduction in the onset melting temperature of both samples with slower heating rates due to HCl and HBr salt disproportionation.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Solid-state epimerisation and disproportionation of pilocarpine HCl: Why we need a 5-stage approach to validate melting point measurements for heat-sensitive drugs

Malallah

Hammond

Al-Adhami

et al. 2020

International Journal of Pharmaceutics

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Solid-state epimerisation and disproportionation of pilocarpine HCl: Why we need a 5-stage approach to validate melting point measurements for heat-sensitive drugs

Malallah

Hammond

Al-Adhami

et al. 2020

International Journal of Pharmaceutics

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“…This is analogous to the well-known pH max of salts, where the salt and free base or free acid solubility curves intersect, and the salt solubility is higher or lower than the non-ionized form of the drug depending on pH and pH max . 2, 34–37 …”

Section: Resultsmentioning

confidence: 99%

Cocrystals Mitigate Negative Effects of High pH on Solubility and Dissolution of a Basic Drug

Chen

Rodrı́guez-Hornedo

2018

Crystal Growth & Design

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Weakly basic drugs are predisposed to order of magnitude decreases in solubility and dissolution as pH increases from 1 to 7 along the gastrointestinal tract. Such behavior is known to be detrimental to drug absorption. The work presented here shows how cocrystals of basic drugs with acidic coformers can mitigate these negative effects. Cocrystals of ketoconazole (KTZ) with adipic, fumaric, and succinic acids exhibit a parabolic solubility dependence on pH such that with increasing pH, solubility decreases, reaches a minimum, and increases. Cocrystals exhibit pHmax values between 3.6 and 3.8, above which they generate supersaturation with respect to drug. Cocrystal supersaturation index (SA), defined as Scocrystal/Sdrug, changes from 1 (pHmax) to 10–30 (pH 5) to 800 – 3,000 (pH 6.5). SA represents the driving force for cocrystal conversion to the less soluble drug during dissolution. SA is not expected to be equal to the observed supersaturation, but it is of great value to classify cocrystals in terms of their risk of conversion. Cocrystal dissolution behavior was analyzed in terms of Cmax, σmax (maximum KTZ concentration and supersaturation), AUCdiss (KTZ concentration area under the curve during dissolution-precipitation), and SA. The three cocrystals studied achieved σmax values between 5 and 15 and sustained supersaturation for 1 to 3 h, resulting in AUCdiss advantage over drug in the range of 2 to 12. SA values as high as 800 were associated with enhanced drug exposure. SA of 3,000 led to limited exposure, very rapid conversion, and no measurable supersaturation. Since cocrystals may be more soluble than needed and/or too soluble to be developed, there is great value in recognizing the relationship between supersaturation threshold, cocrystal solubility, and SA. This becomes more important as cocrystal SA is dependent on pH and other environmental conditions.

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“…Salt formation is a well-known strategy to increase the solubility of either lipophilic weak acids or bases in order to improve oral absorption. Nevertheless, the expected benefits of forming a salt may not work if the level of supersaturation leads to drug precipitation to the free acid or base, thereby reducing the drug exposure levels for absorption [14,15,16]. The “supersaturation/precipitation interactive process” depends on the characteristics of the weak acid or base and, not unimportant, on the dissolution study design with respect to media composition and hydrodynamics that will determine the bulk and interfacial pH around the dissolving particles.…”

Section: Resultsmentioning

confidence: 99%

Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways Analyses

et al. 2019

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The present work aimed to explain the differences in oral performance in fasted humans who were categorized into groups based on the three different drug product formulations of dexketoprofen trometamol (DKT) salt—Using a combination of in vitro techniques and pharmacokinetic analysis. The non-bioequivalence (non-BE) tablet group achieved higher plasma Cmax and area under the curve (AUC) than the reference and BE tablets groups, with only one difference in tablet composition, which was the presence of calcium monohydrogen phosphate, an alkalinizing excipient, in the tablet core of the non-BE formulation. Concentration profiles determined using a gastrointestinal simulator (GIS) apparatus designed with 0.01 N hydrochloric acid and 34 mM sodium chloride as the gastric medium and fasted state simulated intestinal fluids (FaSSIF-v1) as the intestinal medium showed a faster rate and a higher extent of dissolution of the non-BE product compared to the BE and reference products. These in vitro profiles mirrored the fraction doses absorbed in vivo obtained from deconvoluted plasma concentration–time profiles. However, when sodium chloride was not included in the gastric medium and phosphate buffer without bile salts and phospholipids were used as the intestinal medium, the three products exhibited nearly identical concentration profiles. Microscopic examination of DKT salt dissolution in the gastric medium containing sodium chloride identified that when calcium phosphate was present, the DKT dissolved without conversion to the less soluble free acid, which was consistent with the higher drug exposure of the non-BE formulation. In the absence of calcium phosphate, however, dexketoprofen trometamol salt dissolution began with a nano-phase formation that grew to a liquid–liquid phase separation (LLPS) and formed the less soluble free acid crystals. This phenomenon was dependent on the salt/excipient concentrations and the presence of free acid crystals in the salt phase. This work demonstrated the importance of excipients and purity of salt phase on the evolution and rate of salt disproportionation pathways. Moreover, the presented data clearly showed the usefulness of the GIS apparatus as a discriminating tool that could highlight the differences in formulation behavior when utilizing physiologically-relevant media and experimental conditions in combination with microscopy imaging.

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Salt disproportionation: A material science perspective

Cited by 40 publications

References 63 publications

Solid-state epimerisation and disproportionation of pilocarpine HCl: Why we need a 5-stage approach to validate melting point measurements for heat-sensitive drugs

Solid-state epimerisation and disproportionation of pilocarpine HCl: Why we need a 5-stage approach to validate melting point measurements for heat-sensitive drugs

Cocrystals Mitigate Negative Effects of High pH on Solubility and Dissolution of a Basic Drug

Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways Analyses

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