Cyclodextrins and Their Derivatives as Drug Stability Modifiers

**Background:** Drug stability is a critical quality attribute affecting efficacy, safety, and formulation choices. Many active pharmaceutical ingredients (APIs) are susceptible to chemical degradation (hydrolysis, oxidation, photodegradation) or physical instability (phase transformation). Cyclodextrins (CDs) are cyclic oligosaccharides with a hydrophilic exterior and hydrophobic cavity that can form inclusion complexes with drugs, potentially modifying their stability. However, CDs can either stabilize or destabilize drugs depending on the specific drug–CD interaction. This narrative review summarizes the impact of native and modified CDs on the chemical and physical stability of various drugs, including biological products, herbal compounds, cosmetic ingredients, photodynamic therapy agents, and synthetic APIs.

**Methods:** This is a narrative review that compiles and discusses findings from published studies on CD–drug complexes and their effects on stability. The authors describe the structure and properties of native CDs (αCD, βCD, γCD) and modified CDs (HPβCD, MβCD, CMβCD, SBEβCD, DMβCD, RMβCD, etc.). They review examples from the literature where CDs improved stability (e.g., by inhibiting aggregation, reducing hydrolysis, enhancing photostability) and cases where CDs accelerated degradation. The review also covers multicomponent complexes (e.g., with amino acids, polymers, organic bases) that can further modulate stability.

**Key Results:** The review presents numerous examples: - **Biological products:** CDs inhibited aggregation of Clostridium difficile Toxoid A, V antigen, FGF-10, human growth hormone, and IgG. Glucagon complexed with γCD showed improved chemical half-life at pH 2.0 and extended lag-time before aggregation at pH 2.5. Insulin glargine with SBEβCD reduced enzymatic degradation at the injection site. - **Herbal compounds:** Z-ligustilide photostability improved with HPβCD (degradation 77.9% free vs. 22.2% complexed after 6 days). Resveratrol with SBEβCD showed a 27-fold increase in drug levels after 8 days at pH 7.4 and a 4-fold increase in half-life in plasma. Oxyresveratrol with HPβCD protected against degradation over 30 days at 4–50°C. Quercetin and resveratrol with HPβCD and hyaluronic acid showed prolonged half-lives in PBS pH 7.4. Rutin photostability improved 2.5-fold with βCD and 5.4-fold with HPβCD under UVB. - **Cosmetic products:** UV filters (oxybenzone, octocrylene, ethylhexyl-methoxycinnamate) showed increased photostability with βCD. Phenylbenzimidazole sulfonic acid with HPβCD significantly reduced photodegradation and maintained stability for 6 months. Tretinoin with βCD showed increased stability under fluorescence and UV light. - **Photodynamic therapy:** Tetra-1,2-diethylamino substituted zinc(II) phthalocyanine with βCD showed superior stability due to more hydrogen bonds. - **Synthetic APIs:** Enalapril with βCD was 2.1 times more stable in solution and prevented cyclization in solid state (95% recovery vs. 82% for pure drug). Hydrocortisone with HPβCD decreased hydrolysis rate constant in PBS pH 7.4; HPβCD also increased stability after gamma irradiation. Famotidine with HPβCD or CMβCD reduced acidic degradation, but SBEβCD induced destabilization. Lansoprazole with HPβCD showed better photostability than with βCD. Camptothecin with RDMβCD showed a 10-fold increase in stability at 25% w/v. Nintedanib with SBEβCD enhanced stability in simulated intestinal fluid. Posaconazole with βCD increased stability via computational simulation. Nicardipine photostability was improved by βCD, HPαCD, and 2-hydroxyethyl-βCD, but αCD promoted photodegradation. Doxycycline hyclate with βCD showed 98% recovery vs. 68% for pure drug after 6 h UV. Oxytetracycline hydrochloride form III with βCD increased half-time by 20 h. Doxorubicin with HPβCD degraded three times slower. Furosemide multicomponent complex with βCD and triethanolamine showed higher stabilization than binary complexes. Ascorbic acid with HPβCD increased half-life from 3.4 h to 10.0 h at 1% HPβCD; multicomponent with triethanolamine showed 11- and 35-fold photostability increases. Dihydroartemisinin multicomplex with HPβCD and soybean lecithin had k values of 0.48 (pure), 0.38 (binary), and 0.13 h⁻¹ (multicomponent). - **Degradation induced by CDs:** Benzylpenicillin with HPβCD reduced hydrolysis at pH 1.2–4.6 but accelerated at pH 7.4 and 9.6; RMβCD showed less catalytic effect. Methylated γCD derivatives showed 3-fold increase in stability. β-Lactam antibiotics degraded faster with βCD. Cefixime with βCD (freeze-drying) accelerated degradation. Rifampicin with γCD reduced stability, but multicomplex with arginine avoided this. Norfloxacin C with βCD increased photostability, but norfloxacin B hydrate was destabilized. Omeprazole degradation was accelerated by βCD, DMβCD, HPβCD, and MaβCD (order: βCD > DMβCD > MaβCD > HPβCD). Prostaglandins were destabilized by βCD but stabilized by DMβCD. Irbesartan and candesartan cilexetil with γCD and organic salts (Tris, sodium acetate) showed increased solubility but chemical instability at high salt concentrations.

**Clinical Implications:** The review highlights that CDs are versatile excipients that can significantly improve the stability of many drugs, enabling better formulation, storage, and therapeutic efficacy. However, the effect is highly dependent on the specific CD, drug, and conditions. For clinical use, careful selection of CD type, degree of substitution, and concentration is essential. Multicomponent complexes offer additional opportunities to fine-tune stability. The findings underscore the need for systematic screening and molecular modeling to identify optimal CD–drug combinations. This knowledge can guide the development of more stable pharmaceutical products, including biologics, herbal medicines, and synthetic drugs, ultimately improving patient outcomes.