A Dual Approach of Salt Formation and Amorphous Solid Dispersion for Improved Oral Drug Delivery

Poorly water-soluble drugs are characterized by their limited dissolution in the gastrointestinal (GI) tract that causes reduced bioavailability and suboptimal therapeutic outcomes. Drug solubility is a crucial factor that influences the absorption and bioavailability of orally administered drugs. For a drug to be absorbed, it must first dissolve in the GI fluid and then permeate through the intestinal membrane. Poorly water-soluble drugs often exhibit dissolution-limited absorption, meaning their dissolution rate is the rate-limiting step in the absorption process. Moreover, the prevalence of poorly water-soluble drugs has been increasing. Recent drug discovery efforts focus on highly lipophilic and structurally complex compounds that often exhibit low solubility. Therefore, it is important to address the problem of poor water solubility. This project explores an integrated approach to solve this issue by combining salt formation and amorphous solid dispersion. Three weakly basic belonging to BCS class II drugs, clofazimine, aripiprazole, and haloperidol, were selected as model drugs. Ten salts of each drug were prepared with counterions with ΔpKa> 3 using a rotary evaporator and characterized for thermal analysis, structural analysis, and equilibrium drug solubility. Clofazimine mesylate, aripiprazole tartrate, and haloperidol tartrate were the highest soluble salts with 84, 3500, and 400-fold increase in drug solubility, respectively. These salts were used with hot melt extrusion to prepare three different dispersions: amorphous solid dispersions (ASD), in situ salt solid dispersions (SSD), and preformulated SSD. Where SSD is the combination of salt formation and amorphous solid dispersions. The formulations were characterized for thermal and structural analysis, equilibrium solubility, and release studies at pH 1.2. (0.1 N HCL). The SSDs of all the drugs showed a significant enhancement in the aqueous solubility and dissolution compared to the individual drugs. Clofazimine mesylate in-situ SSD was 1500 times more soluble than the free base, while aripiprazole tartrate pre-formulated SSD was 400 times more soluble than aripiprazole. The release of haloperidol tartrate in-situ SSD was significantly greater than the free base, ASD, and pre-formulated SSD. Therefore the dual approach of salt formation proved beneficial for the solubility enhancement of all the model drugs

Grantor dc:publisher

Creighton University

Year dc:date.issued

2023

Author dc:creator

• Panchabhai, Neha Shrikrishna

Advisor dc:contributor.advisor

• Tolman, Justin A.

• Amorphous Solid Dispersion
• Integrated Approach
• Salts

Statement dc:rights

• Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.

Language dc:language.iso

en_US

Repository record dc:identifier.uri

https://cdr.creighton.edu/handle/10504/153993

OAI identifier oai:identifier

oai:cdr.creighton.edu:10504/153993