Recrystallization of Drugs: Significance on Pharmaceutical Processing

Javadzadeh, Yousef; Hamedeyazdan, Sanaz; Asnaashari, Solmaz

doi:10.5772/33156

Cited by 5 publications

(5 citation statements)

References 51 publications

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“…Recrystallization of Broflanilide (1). Considering the importance of recrystallization in the development and application of drugs 17 and to validate the structure of our product, we tried to obtain 1 in a crystalline form. The best solvent for recrystallization was defined by screening the solubility of 1 in a range of solvents, including DMF, DCM, diethyl ether, methanol, ethyl alcohol, acetone, isopropanol, and the mixed solvents of ethanol−water, methanol−water, and isopropanol−water.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…1 H NMR (400 MHz, DMSO-d 6 ) δ 10.75 (s, 1H), 8.40−8.36 (m, 1H), 8.24−8.06 (m, 3H), 7.97 (d, J = 2.2 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H). 13 3-Amino-2-fluoro-N-(4-(perfluoropropan-2-yl)-2-(trifluoromethyl)phenyl)benzamide (17). Intermediate 16 obtained from the previous step, 5.0 wt % Pd/C (4.80 g, approximately 50% water), and CH 3 OH (1.8 L) were combined in an autoclave.…”

Section: ■ Conclusionmentioning

confidence: 99%

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Development of an Efficient Synthetic Process for Broflanilide

Luo

Huang

et al. 2020

Org. Process Res. Dev.

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This article describes the development of an efficient and scalable synthetic route to the novel insecticide broflanilide (1). This redesigned synthetic sequence starts from 2-fluoro-3-nitrobenzoic acid and 4-(perfluoropropan-2-yl)-2-(trifluoromethyl) aniline and provides the target product in a high overall yield through condensation, nitro group reduction, N-methylation, amidation, and subsequent bromination steps. The desired amide moiety is established under mild conditions, and imide generation is avoided. Using paraformaldehyde and Pt/C for N-methylation and NaBr-NaClO for bromination increased the industrial suitability of this route. Unlike existing routes, this new route requires isolation at only six steps (including the heptafluorination), and the overall yield was 60.3%, representing a significant improvement. Broflanilide (1) crystals were obtained from recrystallization in 98% aqueous CH3OH, and the structure was confirmed by X-ray analysis. This work provides a reliable strategy for the large-scale manufacturing of broflanilide (1).

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

Development of an Efficient Synthetic Process for Broflanilide

Luo

Huang

et al. 2020

Org. Process Res. Dev.

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“…Recrystallization of PBRM. Considering the advantages of recrystallization in the development of a drug candidate, especially regarding chemistry, manufacturing, and control, 32 we were highly interested in obtaining PBRM in a crystal form. Identification of a valuable solvent of recrystallization was thus explored by screening the solubility of PBRM in a range of organic solvents, including DCM, DMF, EtOAc, ACN, diethyl ether, methanol, toluene, and acetone.…”

Section: Resultsmentioning

confidence: 99%

Development of a Gram-Scale Synthesis of PBRM, an Irreversible Inhibitor of 17β-Hydroxysteroid Dehydrogenase Type 1

Maltais

Poirier

2019

Org. Process Res. Dev.

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Efforts toward the development of a reliable gram-scale synthesis of 3-{[(16β,17β)-3-(2-bromoethyl)-17-hydroxyestra-1,3,5(10)-trien-16-yl]methyl}benzamide (PBRM), a potent and selective steroidal covalent inhibitor of 17β-hydroxysteroid dehydrogenase type 1, are described. Among the three synthetic routes (C–E) developed herein, route E is the most efficient one with only six chemical steps from commercially available estrone, and an overall yield of 13% leading to PBRM with a high-HPLC-grade purity (99.7%) after recrystallization. Important improvements have been achieved in this sequence from previously reported routes (A and B). Notably, we used a palladium-catalyzed Suzuki–Miyaura cross-coupling reaction to rapidly install the requested C3 chain on estrone. Also, catalytic hydrogenation of the C16-enone was shortened by half using Pearlman’s catalyst. Finally, we used a selective bromination through deoxygenation of alcohol at the last step of the sequence to provide PBRM without dehydration of its carboxamide functionality, a persistent problem observed in other routes. Crystals of PBRM were also obtained from recrystallization in acetonitrile and submitted to X-ray analysis, which confirmed the PBRM structure. This work now makes it possible to start a proof-of-principle in a nonhuman primate model for the treatment of endometriosis, while supporting its future pharmacological development.

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“…25 Tetapi obat padatan amorf dapat berubah menjadi padatan kristal selama penyimpanan, di mana perubahannya tidak selalu melewati semua tahapan metastabil, tetapi dapat melompat menjadi bentuk yang tidak stabil sehingga kelarutannya menjadi rendah dalam medium. 26 Kelembapan mungkin dapat mendorong pembentukan kristal dari farmaseutikal amorf. Fase pembentukan kristal obat ke bentuk yang lebih stabil dari bentuk kristal metastabil selama proses penyimpanan merupakan hambatan utama karena dapat menyebabkan kelarutan dan disolusi akan menurun.…”

Section: Penelitian Dari Dasunclassified

Disolusi Kapsul Dispersi Padat Piroksikam-PEG 6000 Selama Penyimpanan

Binarjo

Khotimah²

2017

IJPST

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AbstrakKelarutan piroksikam yang rendah mempengaruhi laju disolusi sebagai penentu bioavaibilitas. Pembuatan dispersi padat dengan piroksikam-polietilenglikol dapan meningkatkan laju disolusinya. Tujuan penelitian ini adalah untuk mengetahui pengaruh pembentukan dispersi padat piroksikampolietilenglikol 6000 (PEG 6000) terhadap laju disolusi kapsul piroksikam selama 1 bulan penyimpanan. Rekristal piroksikam (R) dan dispersi padat piroksikam-PEG 6000 (DP) dibuat dengan metode pelarut menggunakan campuan aseton-etanol (1:1), keduanya bersama dengan piroksikam tanpa modifikasi (P) dikapsul dan disimpan selama 1 bulan. Uji disolusi dilakukan setiap minggu. Efisiensi disolusi 60 menit (DE60), prosentase disolusi 45 menit (C45), dan waktu untuk 80% terdisolusi (t80) digunakan sebagai parameter disolusi. Kurva hubungan DE60, C45, dan t80 terhadap waktu penyimpanan dilihat slopenya sebagai parameter stabilitas. Hasil percobaan menunjukkan bahwa Kapsul P dan DP menunjukkan nilai DE60, C45, dan t80 yang stabil selama penyimpanan (slope=0, p>0.05), demikian juga nilai t80 kapsul R. Sedangkan DE60 dan C45 kapsul R selama penyimpanan terus menurun dengan slope -0,636 %/hari dan -0,171 mg/hari. Dapat disimpulkan bahwa DP yang dibuat dengan metode pelarut campuran aseton dan etanol (1:1) menunjukkan profil disolusi yang stabil selama penyimpanan 1 bulan.. Kata kunci : disolusi, piroksikam, dispersi padat, polietilenglikol 6000, stabilitas Dissolution Of Solid Dispersion Piroxicam-PEG 6000 Capsules During Storage AbstractThe low solubility of piroxicam affect its rate of dissolution as bioavailability limiting factor. Solid dispersion using polyethilenglycol can improve its dissolution rate. This research was aimed to determine the effect of piroxicam-polyethylenglycol 6000 (PEG 6000) solid dispersion formation on the dissolution rate of piroxicam capsules during storage for 1 month. The piroxicam recrystal (R) and solid dispersion of piroxicam-PEG 6000 (DP) were prepared by solvent method using acetone-ethanol (1:1), these two bulk and unmodified piroxicam (P) as control than be capsulated and stored for 4. Their dissolution were tested every week. Sixty minutes dissolution efficiency (DE60), percent drug dissolved in 45 minutes (C45), and time to dissolve 80% of drug (t80) were used as dissolution parameters. The slope of the plot of these dissolution parameters as a function of time storage was used as a stability indicator. The result show that P and DP capsules have a constant DE60, C45, and t80 during storage (slope=0, p>0.05), also the data of t80 of R capsule. DE60 and C45 of R capsule is going lower during the storage with the slope of -0,636 %/day and -0,171 mg/day. It can be concluded that DP prepared by solvent method using acetoneethanol (1:1) shows the stable dissolution profiles during storage for 1 month.

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Recrystallization of Drugs: Significance on Pharmaceutical Processing

Cited by 5 publications

References 51 publications

Development of an Efficient Synthetic Process for Broflanilide

Development of an Efficient Synthetic Process for Broflanilide

Development of a Gram-Scale Synthesis of PBRM, an Irreversible Inhibitor of 17β-Hydroxysteroid Dehydrogenase Type 1

Disolusi Kapsul Dispersi Padat Piroksikam-PEG 6000 Selama Penyimpanan

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