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Title: The Effects of Humidity on Spontaneous Cocrystallization: A Survey of Diacid Cocrystals with Caffeine, Theophylline, and Nicotinamide
Pharmaceutical cocrystals comprise one active pharmaceutical ingredient (API) and at least one small molecule excipient coformer. While solvent evaporation and mechanochemistry are the preferred methods for their synthesis, some cocrystals are known to form spontaneously at ambient conditions when powders of input materials are mixed—a process not yet fully understood. Aqueous humidity is also known to accelerate spontaneous cocrystal formation. We report here the extent of spontaneous cocrystallization for 14 cocrystal systems, at four levels of humidity. The binary cocrystals in our study consist of a model API (caffeine, theophylline, nicotinamide) and a small chain diacid coformer (oxalic acid, malonic acid, maleic acid, fumaric acid, succinic acid, glutaric acid). The spontaneous cocrystal formation was monitored ex situ by powder X-ray diffraction over several weeks. Our results show cocrystal formation in all 14 systems to varying extent and are consistent with literature reports that higher humidity correlates with more rapid cocrystal formation. We find that cocrystals containing smaller coformers often form faster. Based on our findings, we identify several cocrystals as candidates for future study.  more » « less
Award ID(s):
2100582
NSF-PAR ID:
10328901
Author(s) / Creator(s):
; ; ; ;
Date Published:
Journal Name:
Journal of Chemical Crystallography
ISSN:
1074-1542
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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    To what extent is male fatty acid intake associated with fecundability among couples planning pregnancy?

    SUMMARY ANSWER

    We observed weak positive associations of male dietary intakes of total and saturated fatty acids with fecundability; no other fatty acid subtypes were appreciably associated with fecundability.

    WHAT IS KNOWN ALREADY

    Male fatty acid intake has been associated with semen quality in previous studies. However, little is known about the extent to which male fatty acid intake is associated with fecundability among couples attempting spontaneous conception.

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    We conducted an internet-based preconception prospective cohort study of 697 couples who enrolled during 2015–2022. During 12 cycles of observation, 53 couples (7.6%) were lost to follow-up.

    PARTICIPANTS/MATERIALS, SETTING, METHODS

    Participants were residents of the USA or Canada, aged 21–45 years, and not using fertility treatment at enrollment. At baseline, male participants completed a food frequency questionnaire from which we estimated intakes of total fat and fatty acid subtypes. We ascertained time to pregnancy using questionnaires completed every 8 weeks by female participants until conception or up to 12 months. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs for the associations of fat intakes with fecundability, adjusting for male and female partner characteristics. We used the multivariate nutrient density method to account for energy intake, allowing for interpretation of results as fat intake replacing carbohydrate intake. We conducted several sensitivity analyses to assess the potential for confounding, selection bias, and reverse causation.

    MAIN RESULTS AND THE ROLE OF CHANCE

    Among 697 couples, we observed 465 pregnancies during 2970 menstrual cycles of follow-up. The cumulative incidence of pregnancy during 12 cycles of follow-up after accounting for censoring was 76%. Intakes of total and saturated fatty acids were weakly, positively associated with fecundability. Fully adjusted FRs for quartiles of total fat intake were 1.32 (95% CI 1.01–1.71), 1.16 (95% CI 0.88–1.51), and 1.43 (95% CI 1.09–1.88) for the second, third, and fourth vs the first quartile, respectively. Fully adjusted FRs for saturated fatty acid intake were 1.21 (95% CI 0.94–1.55), 1.16 (95% CI 0.89–1.51), and 1.23 (95% CI 0.94–1.62) for the second, third, and fourth vs the first quartile, respectively. Intakes of monounsaturated, polyunsaturated, trans-, omega-3, and omega-6 fatty acids were not strongly associated with fecundability. Results were similar after adjustment for the female partner’s intakes of trans- and omega-3 fats.

    LIMITATIONS, REASONS FOR CAUTION

    Dietary intakes estimated from the food frequency questionnaire may be subject to non-differential misclassification, which is expected to bias results toward the null in the extreme categories when exposures are modeled as quartiles. There may be residual confounding by unmeasured dietary, lifestyle, or environmental factors. Sample size was limited, especially in subgroup analyses.

    WIDER IMPLICATIONS OF THE FINDINGS

    Our results do not support a strong causal effect of male fatty acid intakes on fecundability among couples attempting to conceive spontaneously. The weak positive associations we observed between male dietary fat intakes and fecundability may reflect a combination of causal associations, measurement error, chance, and residual confounding.

    STUDY FUNDING/COMPETING INTEREST(S)

    The study was funded by the National Institutes of Health, grant numbers R01HD086742 and R01HD105863. In the last 3 years, PRESTO has received in-kind donations from Swiss Precision Diagnostics (home pregnancy tests) and Kindara.com (fertility app). L.A.W. is a consultant for AbbVie, Inc. M.L.E. is an advisor to Sandstone, Ro, Underdog, Dadi, Hannah, Doveras, and VSeat. The other authors have no competing interests to report.

    TRIAL REGISTRATION NUMBER

    N/A.

     
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