# An Optimization Approach for the Production of High-Purity Vitamin C‑Nicotinamide Cocrystals by the Gas Antisolvent (GAS) Technique with CO2 and Ethanol

## TL;DR

Scientists optimized a method to produce high-purity vitamin C cocrystals using carbon dioxide and ethanol, improving stability and yield for potential health applications.

## Contribution

A novel optimization of the GAS technique for producing high-purity vitamin C-nicotinamide cocrystals with improved yield and stability.

## Key findings

- High-purity (>99%) vitamin C-nicotinamide cocrystals were produced using optimized GAS conditions.
- The maximum cocrystal yield of 85.2% was achieved at 80 bar pressure with ethanol as the solvent.
- The cocrystals showed fine particle size, thermal stability, and preserved antioxidant properties without cytotoxicity.

## Abstract

Vitamin C (l-ascorbic acid, ASC) is a powerful
antioxidant
nutrient with diverse metabolic functions, regenerative properties,
and anticancer potential. However, it is a highly unstable molecule.
ASC can form a cocrystal with the amide of vitamin B3 (nicotinamide,
NIC) through self-complementary hydrogen bonding, therefore improving
its physical stability. Pressurized carbon dioxide (CO2), via the gas antisolvent (GAS) method, makes an excellent medium
for cocrystallizing vitamins, particularly from ethanolic solutions.
However, the controllable variables of the GAS method should be optimized
for a feasible process. The production of the ASC:NIC cocrystal was
optimized using a Box–Behnken experimental design (BBD) at
90 bar and with ethanol as the solvent while varying the temperature,
CO2 flow rate, and ASC:NIC molar ratio. The final ASC and
NIC contents in the cocrystals were determined by derivative spectrophotometry
and supported by HPLC and elemental analysis. PXRD and DSC confirmed
that high-purity (>99%) cocrystals can be produced by setting a
proper
initial molar ratio of starting compounds. The maximum cocrystal yield
by GAS (85.2%) was attained at the optimized condition using a lower
pressure (80 bar) due to higher supersaturation of the system. Purest
cocrystals exhibited a needle-like morphology, fine particle size,
and thermal stability while preserving the antioxidant power of ASC
with high crystallinity and displaying no cytotoxicity to healthy
epithelial cells up to 0.5 mM. GAS with CO2/ethanol could
be optimized to overcome the solubility discrepancies between ASC
and NIC in ethanol, producing vitamin C cocrystals at higher yields
with a marked potential for nutritional and pharmaceutical applications.