Introduction
Itraconazole (Figure 1) is an antifungal agent widely used in paediatric patients for the treatment of various fungal infections, including tinea capitis that is refractory to terbinafine treatment1. Its efficacy in children makes it a crucial medication, particularly for those under five years of age, where treatment options are limited. The recommended dosage of itraconazole is 5 mg/kg/day, administered as a single dose not exceeding 100 mg1.
The commercial formulation of itraconazole, Sporanox (Janssen-Cilag, Issy-Les-Moulineaux, France), was previously available in a 10 mg/mL oral solution form. However, the discontinuation of this oral solution in 2025 has created a significant gap in the availability of appropriate formulations for paediatric patients. Given that children under five years of age often have difficulty swallowing tablets or capsules, the development of a suitable liquid formulation is essential2.
Itraconazole is classified as a Class 2 drug according to the Biopharmaceutics Classification System (BCS), indicating low solubility but high permeability, which presents challenges for formulation and administration, particularly in paediatric patients3.
To overcome these challenges, GlaxoSmithKline Pharmaceuticals developed a solid solution to amorphize itraconazole and enhance its bioavailability4, while Janssen-Cilag formulated an amorphous solid dispersion (ASD) for the same purpose5.Commercial formulations of itraconazole, such as Sporanox capsules, exhibit a maximum bioavailability of 55% when taken with food, highlighting the importance of diet in enhancing drug absorption. In contrast, the oral solution (a cyclodextrin-based formulation) demonstrates the same bioavailability, which increases by 30% when not taken with food1. This may be due to interactions between the cyclodextrin complex and the food components, which could potentially affect the stability of the formulation and re-precipitate the itraconazole in vivo.
Understanding Solid-State Polymorphism
Solid-state is a property of matter that refers to substances with a fixed shape and volume. Solids can be amorphous (lacking a long-range ordered lattice structure) or crystalline.
Solid-state polymorphism is the ability of a drug to exist in multiple crystalline forms. It plays a critical role in pharmaceutical development, directly impacting drug bioavailability, stability. Polymorphism arises when a compound crystallizes in more than one lattice arrangement, leading to forms with distinct physicochemical properties such as melting point, solubility, dissolution rate, and stability6.
Impact on Bioavailability: Polymorphic forms can differ significantly in solubility and dissolution rate, which are key determinants of oral bioavailability for drugs belonging to the BCS class II or IV (low solubility)3. Amorphous solid or metastable polymorphs often have higher solubility and faster dissolution, potentially enhancing absorption, but may convert to more stable, less soluble forms over time, risking reduced or variable bioavailability6.
Impact on Stability: The stability of a drug product is closely tied to the thermodynamic stability of its polymorphic form. Metastable forms, while sometimes desirable for their solubility, are prone to transformation into more stable forms during manufacturing, storage, or even in vivo, potentially leading to loss of efficacy or product failure7. Regulatory agencies require comprehensive screening and control of polymorphic forms to ensure consistent product quality and performance7. This conversion phenomenon can occur during the dissolution–reprecipitation of liquid formulations, such as solutions exposed to thermodynamic changes (e.g. freezing or refrigeration). This phenomenon can also occur in suspensions, where the active substance undergoes partial dissolution followed by reprecipitation. Working at a pH that is unfavourable to the dissolution and adding crystallization inhibitors such as povidone (PVP) may therefore be recommended.
Case Study: Compounding Itraconazole liquid formulations for Paediatric Use
To address the need and mitigate the shortage, three practical formulation options may be considered :
Compound a suspension from pharmaceutical-grade itraconazole API in a specially designed or a commercially available vehicles.
- Pros: Fast to implement, inexpensive, may be a familiar workflow.
- Limits: API remains in its solid state (BCS Class II) → variable dissolution and absorption; sedimentation/shaking issues; bioavailability not assured.
Suspensions prepared from raw pharmaceutical-grade itraconazole may appear physically stable yet biopharmaceutically suboptimal due to dissolution-limited absorption. The crystalline polymorphs typically found in raw API exhibit extremely low and pH-dependent aqueous solubility, decreasing from about 4 µg/mL at pH 1.2 to less than 0.1 µg/mL above pH 4.5, and becoming practically insoluble at intestinal pH 6–78 leading to erratic dissolution, poor and unpredictable oral absorption9.
Compound a suspension by dispersing commercial solid dosage forms (e.g. capsule pellets) of itraconazole in a specially designed or a commercially available vehicles.
- Pros: Uses a form with known clinical performance in its intended presentation.
- Limits: Many itraconazole capsules contain coated pellets designed for specific gastric/intestinal release; dispersing them can alter release and absorption, create dosing non-uniformity issues, and may be off-label/not recommended by the Good Compounding Practice.
Christensen et al. compared the bioavailability of an extemporaneous itraconazole suspension to that of marketed capsules and found that the suspension’s AUC and Cₘₐₓ were only ≈ 0.12–0.15 of the capsule values, showing very low systemic exposure from the suspension form10.
Reverse engineer an oral solution similar to the former Sporanox® formulation (e.g. HP-β-cyclodextrin with acidifier ± propylene glycol).
- Pros: Typically yields higher and more consistent bioavailability than simple suspensions if properly formulated and validated.
- Limits: Requires solid-state/solubility work, stability and compatibility studies, and access to suitable excipients; regulatory/quality requirements for compounding must be met.
When preparing HP-β-cyclodextrin solutions, the the sequence of solubilization and complexation steps critically affects complexation efficiency: pre-dissolving itraconazole in a suitable solvent (e.g. acidified propylene glycol) before complexation yields substantially higher apparent solubility than simple co-dissolution; ~10 mg/mL is achievable only under specific conditions9,11.
Practical recommendations for compounding
- Suspending raw crystalline itraconazole in a vehicle should be avoided, as per literature findings.
- Suspending solid oral dosage forms may be considered, but with caution and thorough evaluation regarding the loss of bioavailability already described in the literature.
- Cyclodextrin based solutions remain feasible with careful monitoring of potential recrystallization of already dissolved itraconazole due to conservation change (e.g. pH change, temperature change)
Conclusion
This case study highlights the essential role of :
Preformulation studies centred on biopharmaceutics and formulation science. They play a crucial role in uncovering both formulation challenges and pharmacokinetic pitfalls.
Solid-state characterization in pharmaceutical compounding. The physical form of an active ingredient, whether polymorphic or amorphous, has a decisive impact on solubility and, consequently, on potential bioavailability, a key consideration for BCS Class II drugs.
In hospitals, the apparent simplicity of suspensions can be misleading when the API is poorly soluble or crystallographically stable.
Ultimately, this reflects the essence of pharmaceutical expertise: transforming a compliant raw material into a clinically reliable medicine through rigorous and informed formulation science.