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Linking Crystal Structure to Solubility and Hygroscopicity in Oxytetracycline Hydrochloride Forms

Pęczek, Martyna ; Butkiewicz, Helena ; Malinska, Maura ; Trzybiński, Damian ; Sławiński, Wojciech A. ; Madsen, Anders ; Gjo̷rup, Frederik H. LU orcid ; Bizoń, Teresa and Hoser, Anna A. (2026) In Crystal Growth and Design 26(1). p.54-67
Abstract

The present study was motivated by the unusually large differences in solubility observed between two polymorphic forms of an antibiotic active pharmaceutical ingredient, oxytetracycline hydrochloride. These differences significantly exceed typical polymorphic solubility variations. Through detailed structural analysis, we demonstrate that forms I and II are not true polymorphs but pseudopolymorphs: anhydrous salt of oxytetracycline hydrochloride (OxyCl) and its hydrate (2OxyCl·3H2O). In the course of this work, we also crystallized and characterized three new structures of hydrates, as well as one methanol and one ethanol solvate of oxytetracycline hydrochloride. Having determined the crystal structures of all known forms... (More)

The present study was motivated by the unusually large differences in solubility observed between two polymorphic forms of an antibiotic active pharmaceutical ingredient, oxytetracycline hydrochloride. These differences significantly exceed typical polymorphic solubility variations. Through detailed structural analysis, we demonstrate that forms I and II are not true polymorphs but pseudopolymorphs: anhydrous salt of oxytetracycline hydrochloride (OxyCl) and its hydrate (2OxyCl·3H2O). In the course of this work, we also crystallized and characterized three new structures of hydrates, as well as one methanol and one ethanol solvate of oxytetracycline hydrochloride. Having determined the crystal structures of all known forms and supplemented this data with XRPD measurements at different humidity levels, we provide new insight into structure–property relationships within this system. Our analysis reveals that solubility and hygroscopicity are closely related to specific features of crystal packing - particularly the thickness of alternating organic and inorganic layers formed through characteristic intermolecular interactions.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Crystal Growth and Design
volume
26
issue
1
pages
14 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:105026661218
ISSN
1528-7483
DOI
10.1021/acs.cgd.5c00785
language
English
LU publication?
yes
id
ca0d7e3e-d8c6-4d2a-b392-dc5579415d99
date added to LUP
2026-03-16 10:07:35
date last changed
2026-03-16 10:08:45
@article{ca0d7e3e-d8c6-4d2a-b392-dc5579415d99,
  abstract     = {{<p>The present study was motivated by the unusually large differences in solubility observed between two polymorphic forms of an antibiotic active pharmaceutical ingredient, oxytetracycline hydrochloride. These differences significantly exceed typical polymorphic solubility variations. Through detailed structural analysis, we demonstrate that forms I and II are not true polymorphs but pseudopolymorphs: anhydrous salt of oxytetracycline hydrochloride (OxyCl) and its hydrate (2OxyCl·3H<sub>2</sub>O). In the course of this work, we also crystallized and characterized three new structures of hydrates, as well as one methanol and one ethanol solvate of oxytetracycline hydrochloride. Having determined the crystal structures of all known forms and supplemented this data with XRPD measurements at different humidity levels, we provide new insight into structure–property relationships within this system. Our analysis reveals that solubility and hygroscopicity are closely related to specific features of crystal packing - particularly the thickness of alternating organic and inorganic layers formed through characteristic intermolecular interactions.</p>}},
  author       = {{Pęczek, Martyna and Butkiewicz, Helena and Malinska, Maura and Trzybiński, Damian and Sławiński, Wojciech A. and Madsen, Anders and Gjo̷rup, Frederik H. and Bizoń, Teresa and Hoser, Anna A.}},
  issn         = {{1528-7483}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{54--67}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Crystal Growth and Design}},
  title        = {{Linking Crystal Structure to Solubility and Hygroscopicity in Oxytetracycline Hydrochloride Forms}},
  url          = {{http://dx.doi.org/10.1021/acs.cgd.5c00785}},
  doi          = {{10.1021/acs.cgd.5c00785}},
  volume       = {{26}},
  year         = {{2026}},
}