Instability in theophylline and carbamazepine hydrate tablets: Cocrystal formation due to release of lattice water

Kapildev K. Arora; Seema Thakral; Raj Suryanarayanan

doi:10.1007/s11095-013-1022-7

Instability in theophylline and carbamazepine hydrate tablets: Cocrystal formation due to release of lattice water

Kapildev K. Arora, Seema Thakral, Raj Suryanarayanan

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

Purpose: To demonstrate two sequential solid-state reactions in intact tablets: dehydration of active pharmaceutical ingredient (API), and cocrystal formation between the anhydrous API and a second formulation component mediated by the released water. To evaluate the implication of this in situ phase transformation on the tablet dissolution behavior. Methods: Tablets containing theophylline monohydrate (TPM) and anhydrous citric acid (CA) were stored at 40 C in sealed polyester pouches and the relative humidity in the headspace above the tablet was continuously measured. Dehydration to anhydrous theophylline (TPA) and the product appearance (TPA-CA cocrystal) were simultaneously monitored by powder X-ray diffractometry. Carbamazepine dihydrate and nicotinamide formed the second model system. Results: The water of crystallization released by TPM dehydration was followed first by deliquescence of citric acid, evident from the headspace relative humidity (~ 68%; 40 C), and then the formation of TPA-CA cocrystal in intact tablets. The noncovalent synthesis resulted in a pronounced decrease in the dissolution rate of theophylline from the tablets. Similarly, the water released by dehydration of carbamazepine dihydrate caused the cocrystallization reaction between anhydrous carbamazepine and nicotinamide. Conclusions: The water released by API dehydration mediated cocrystal formation in intact tablets and affected dissolution behavior.

Original language	English (US)
Pages (from-to)	1779-1789
Number of pages	11
Journal	Pharmaceutical research
Volume	30
Issue number	7
DOIs	https://doi.org/10.1007/s11095-013-1022-7
State	Published - Jul 2013

Bibliographical note

Funding Information:
KKA was partially supported by the William and Mildred Peters Endowment fund. ST gratefully acknowledges the BOYSCAST fellowship awarded by Department of Science and Technology, Govt. of India. We thank Vishard Ragoonanan, Ph.D. and Pinal Mistry for their help. We also thank Dr. John Nelson for his help in recording SEM images. Parts of this work were carried out in the Characterization Facility, University of Minnesota, a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org).

Keywords

carbamazepine dihydrate
cocrystal
dehydration
dissolution
phase transformation
theophylline monohydrate

Access

10.1007/s11095-013-1022-7

OpenUrl availability

Full text

Cite this

@article{073c7852e8e24cbe908b7820fba1fbd5,

title = "Instability in theophylline and carbamazepine hydrate tablets: Cocrystal formation due to release of lattice water",

abstract = "Purpose: To demonstrate two sequential solid-state reactions in intact tablets: dehydration of active pharmaceutical ingredient (API), and cocrystal formation between the anhydrous API and a second formulation component mediated by the released water. To evaluate the implication of this in situ phase transformation on the tablet dissolution behavior. Methods: Tablets containing theophylline monohydrate (TPM) and anhydrous citric acid (CA) were stored at 40 C in sealed polyester pouches and the relative humidity in the headspace above the tablet was continuously measured. Dehydration to anhydrous theophylline (TPA) and the product appearance (TPA-CA cocrystal) were simultaneously monitored by powder X-ray diffractometry. Carbamazepine dihydrate and nicotinamide formed the second model system. Results: The water of crystallization released by TPM dehydration was followed first by deliquescence of citric acid, evident from the headspace relative humidity (~ 68%; 40 C), and then the formation of TPA-CA cocrystal in intact tablets. The noncovalent synthesis resulted in a pronounced decrease in the dissolution rate of theophylline from the tablets. Similarly, the water released by dehydration of carbamazepine dihydrate caused the cocrystallization reaction between anhydrous carbamazepine and nicotinamide. Conclusions: The water released by API dehydration mediated cocrystal formation in intact tablets and affected dissolution behavior.",

keywords = "carbamazepine dihydrate, cocrystal, dehydration, dissolution, phase transformation, theophylline monohydrate",

author = "Arora, {Kapildev K.} and Seema Thakral and Raj Suryanarayanan",

note = "Funding Information: KKA was partially supported by the William and Mildred Peters Endowment fund. ST gratefully acknowledges the BOYSCAST fellowship awarded by Department of Science and Technology, Govt. of India. We thank Vishard Ragoonanan, Ph.D. and Pinal Mistry for their help. We also thank Dr. John Nelson for his help in recording SEM images. Parts of this work were carried out in the Characterization Facility, University of Minnesota, a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org).",

year = "2013",

month = jul,

doi = "10.1007/s11095-013-1022-7",

language = "English (US)",

volume = "30",

pages = "1779--1789",

journal = "Pharmaceutical research",

issn = "0724-8741",

publisher = "Springer New York",

number = "7",

}

TY - JOUR

T1 - Instability in theophylline and carbamazepine hydrate tablets

T2 - Cocrystal formation due to release of lattice water

AU - Arora, Kapildev K.

AU - Thakral, Seema

AU - Suryanarayanan, Raj

N1 - Funding Information: KKA was partially supported by the William and Mildred Peters Endowment fund. ST gratefully acknowledges the BOYSCAST fellowship awarded by Department of Science and Technology, Govt. of India. We thank Vishard Ragoonanan, Ph.D. and Pinal Mistry for their help. We also thank Dr. John Nelson for his help in recording SEM images. Parts of this work were carried out in the Characterization Facility, University of Minnesota, a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org).

PY - 2013/7

Y1 - 2013/7

N2 - Purpose: To demonstrate two sequential solid-state reactions in intact tablets: dehydration of active pharmaceutical ingredient (API), and cocrystal formation between the anhydrous API and a second formulation component mediated by the released water. To evaluate the implication of this in situ phase transformation on the tablet dissolution behavior. Methods: Tablets containing theophylline monohydrate (TPM) and anhydrous citric acid (CA) were stored at 40 C in sealed polyester pouches and the relative humidity in the headspace above the tablet was continuously measured. Dehydration to anhydrous theophylline (TPA) and the product appearance (TPA-CA cocrystal) were simultaneously monitored by powder X-ray diffractometry. Carbamazepine dihydrate and nicotinamide formed the second model system. Results: The water of crystallization released by TPM dehydration was followed first by deliquescence of citric acid, evident from the headspace relative humidity (~ 68%; 40 C), and then the formation of TPA-CA cocrystal in intact tablets. The noncovalent synthesis resulted in a pronounced decrease in the dissolution rate of theophylline from the tablets. Similarly, the water released by dehydration of carbamazepine dihydrate caused the cocrystallization reaction between anhydrous carbamazepine and nicotinamide. Conclusions: The water released by API dehydration mediated cocrystal formation in intact tablets and affected dissolution behavior.

AB - Purpose: To demonstrate two sequential solid-state reactions in intact tablets: dehydration of active pharmaceutical ingredient (API), and cocrystal formation between the anhydrous API and a second formulation component mediated by the released water. To evaluate the implication of this in situ phase transformation on the tablet dissolution behavior. Methods: Tablets containing theophylline monohydrate (TPM) and anhydrous citric acid (CA) were stored at 40 C in sealed polyester pouches and the relative humidity in the headspace above the tablet was continuously measured. Dehydration to anhydrous theophylline (TPA) and the product appearance (TPA-CA cocrystal) were simultaneously monitored by powder X-ray diffractometry. Carbamazepine dihydrate and nicotinamide formed the second model system. Results: The water of crystallization released by TPM dehydration was followed first by deliquescence of citric acid, evident from the headspace relative humidity (~ 68%; 40 C), and then the formation of TPA-CA cocrystal in intact tablets. The noncovalent synthesis resulted in a pronounced decrease in the dissolution rate of theophylline from the tablets. Similarly, the water released by dehydration of carbamazepine dihydrate caused the cocrystallization reaction between anhydrous carbamazepine and nicotinamide. Conclusions: The water released by API dehydration mediated cocrystal formation in intact tablets and affected dissolution behavior.

KW - carbamazepine dihydrate

KW - cocrystal

KW - dehydration

KW - dissolution

KW - phase transformation

KW - theophylline monohydrate

UR - http://www.scopus.com/inward/record.url?scp=84878857969&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878857969&partnerID=8YFLogxK

U2 - 10.1007/s11095-013-1022-7

DO - 10.1007/s11095-013-1022-7

M3 - Article

C2 - 23568521

AN - SCOPUS:84878857969

SN - 0724-8741

VL - 30

SP - 1779

EP - 1789

JO - Pharmaceutical research

JF - Pharmaceutical research

IS - 7

ER -

Instability in theophylline and carbamazepine hydrate tablets: Cocrystal formation due to release of lattice water

Abstract

Bibliographical note

Keywords

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this