# Solubility of Incongruently Melting Active Pharmaceutical Ingredient Cocrystals: The Hydrochlorothiazide–Nicotinamide System

## TL;DR

This study explores how mixing a drug with a coformer can improve its solubility in water, using a specific drug-coformer pair and thermodynamic modeling.

## Contribution

The paper introduces a thermodynamic modeling approach to predict and enhance solubility in incongruently melting drug cocrystals.

## Key findings

- The ternary eutectic composition of HCT–Nic–water provides a solubility enhancement factor of 2.1–2.4.
- Cocrystal dissolution behavior changes with temperature, showing no cocrystal formation at lower temperatures.
- Binary HCT–Nic mixtures yield higher solubility than direct cocrystal dissolution.

## Abstract

Pharmaceutical cocrystallization
is a promising strategy to enhance
the solubility and bioavailability of hydrophobic active pharmaceutical
ingredients (APIs). However, when API–coformer cocrystals exhibit
incongruent melting, understanding and predicting their solubility
in water becomes significantly more complex. In this work, a combined
experimental and thermodynamic modeling approach is presented to investigate
the API solubility enhancement in a ternary API–coformer–water
system. Hydrochlorothiazide (HCT), a biopharmaceutics classification
system (BCS) class IV diuretic, and nicotinamide (Nic), a generally
recognized as safe (GRAS)-listed coformer, were selected as a representative
system that forms an incongruently melting 1:1 cocrystal, which was
confirmed experimentally using differential scanning calorimetry (DSC)
and powder X-ray diffraction (PXRD). Binary solid–liquid equilibrium
(SLE) data for the HCT–Nic, HCT–water, and Nic–water
systems were experimentally measured at different temperatures. The
nonrandom two-liquid (NRTL) model was then used to regress the binary
interaction parameters from the binary SLE data. These parameters
were then used to predict ternary SLE phase diagrams of the HCT–Nic–water
system at 310.15 K, 330.15 K, and 350.15 K. The
NRTL-modeled SLE diagrams revealed the key features of the ternary
system, including the absence of cocrystal formation at 310.15 K
and the emergence of a cocrystal phase region with incongruent dissolution
behavior at elevated temperatures. The highest HCT solubility was
obtained at the ternary API-rich eutectic composition, with a solubility
enhancement factor (Φ) of 2.1–2.4 across the studied
temperatures. In contrast, dissolving the 1:1 cocrystal directly in
water yielded significantly lower solubility enhancements (Φ
≈ 1.0–1.3). These findings clearly demonstrate that
selecting a binary HCT–Nic mixture that, upon dilution in water,
reaches the eutectic composition in the ternary HCT–Nic–water
system yields greater solubility enhancement than starting from the
cocrystal composition. This study emphasizes the importance of thermodynamic
modeling in understanding solubility behavior and guiding the rational
design of cocrystal-based pharmaceutical formulations, especially
for API–coformer systems exhibiting incongruent melting.