The development of oral dosage forms for clinical trials presents a unique set of challenges, particularly in early phases of drug development. Across the pharmaceutical industry, solubility enhancement, content uniformity, and formulation development emerge as critical areas of focus to ensure therapeutic efficacy and patient safety. Poor solubility of active pharmaceutical ingredients (APIs) can limit bioavailability, while inconsistent content uniformity can compromise dosage accuracy, especially in low-dose formulations. These challenges are compounded by the need for robust and scalable manufacturing processes that can accommodate diverse drug delivery requirements.

Formulation development plays a pivotal role in overcoming these obstacles. The following article explores the importance of innovative strategies, such as the use of lipophilic excipients, salt formation, and advanced granulation techniques, to address these formulation hurdles. Together, these insights highlight the interconnected nature of solubility, uniformity, and formulation development, emphasizing their critical importance in the early stages of clinical product development.

Ensuring dispersibility and homogeneity for solutions or suspensions

Orally dosed suspensions can offer advantages over traditional oral solid dosage forms to accommodate specific patient populations, drug delivery requirements or clinical preferences. A suspension is often regarded as a simple dosage form during IND-enabling development and eventual Phase I/II clinical trials. However, ensuring appropriate suspension content uniformity and consistent dosage uniformity can present challenges due to the liquid form of the drug product. Furthermore, as the suspension may be prepared and dosed by the patient or clinical practitioner, the preparation and dosing methods must remain robust and easily transferrable. 

Proper formulation development of a phase-appropriate suspension can ensure appropriate drug substance dispersibility and suspension homogeneity, which will enable consistent dosage uniformity and aid in achieving clinical success. To simplify shipping and reduce the need for shelf-stable formulation and packaging, suspension formulations intended for early phase use are usually packaged in a dry powder-in-bottle configuration, with reconstitution in a selected vehicle occurring at the clinic or with patients. Reconstitution generally occurs by the addition of selected vehicles and handshaking to suspend API.

API agglomeration and settling are the main factors affecting dispersibility and suspension homogeneity. Formulation development of a robust suspension seeks to control these factors. Suspension formulation development generally begins with appropriate vehicle selection. Non-specific vehicles such as juices offer a simple suspension vehicle, however without addition of a surfactant and polymer to mitigate agglomeration and settling, suspendability issues can occur. Table 1 lists the assay and top/middle/bottom content uniformity of a typical API prepared at 10mg/mL in varying suspension vehicles. 

A shown, poor suspension uniformity is observed in orange juice due to API agglomeration and settling (Sample A). A specifically designed suspension vehicle such as SyrSpend is formulated with polymer, surfactant and optional flavoring to disperse and suspend API. Shown as Sample B in Table 1, a 10mg/mL suspension prepared with SyrSpend offered significantly improved suspension homogeneity. If a specialty vehicle such as SyrSpend is not available, preparation techniques such as vehicle sonication and addition of surfactant or defoamer can reduce agglomeration and settling to improve suspension properties. An example (Sample C) is shown in Table 1, where 0.05% T-80 was added to orange juice and the suspension was sonicated. In comparison to neat orange juice, improved suspension properties were observed due to a reduction in agglomerate size, which acted to suspend API despite low vehicle viscosity. Specialty suspension vehicles and preparation techniques such as sonication may not be available at the clinical site. Modification of the powder-in-bottle formulation at the manufacturing site can enable clinical providers to prepare a desirable suspension by simply adding the selected vehicle.

If the API is agglomerated, sieving the API before bottle packaging can improve suspendability and suspension uniformity once reconstituted. Co-sieving the API with a water-soluble excipient such as mannitol can aid in dispersing API when the suspension is prepared by shaking. This simple blend can be customized to determine optimal drug and excipient loading. A simple blend with 40% API and 60% mannitol loading was sieved through a 250µm screen and prepared at 10mg/mL with respect to API concentration in orange juice (Sample D). A decrease in agglomeration and subsequent decreased settling time was observed as higher suspension uniformity versus neat API in orange juice (Sample A). To increase viscosity and modify the thixotropic properties of the vehicle, an advanced blending procedure can cosieve a water-soluble polymer such as xanthan gum with the API. Addition of a low viscosity vehicle at the clinical site such as juice will hydrate the polymer and increase vehicle viscosity, reducing API settling. Sample E is shown in Table 1, which co-sieved xanthan gum in addition to API and mannitol. Slightly improved suspension homogeneity was observed due to increased viscosity and reduced settling. As the physical properties of each API are unique, research and development should be performed to identify an optimal suspension formulation to ensure clinical success.

Optimizing formulations for low dose content uniformity

For low dose solid oral formulations, achieving content uniformity can be a common challenge when creating a low drug loading formulation. Doses below 1mg per unit can necessitate creative formulation solutions to producing a uniform distribution of the drug substance.   

In the following example, a project was undertaken to formulate a 0.3mg immediate release tablet suitable for early phase clinical studies. Top-spray fluid bed granulation was chosen to distribute the drug substance via the granulating solution across the excipient formulation components. In this case the drug substance solubility and stability in solution was amenable to this type of granulation process. Fluid bed granulation allows for precise control of the drug substance addition rate through spray rate control and solution concentration of the process. Additionally, the spray pattern can be readily controlled through the air settings and nozzle selection of the equipment.

Another consideration in this process is the granulation action itself, where clusters of excipient components are created by the binding excipient in the spray solution. To reduce development time and complexity, the granulation process was minimized by intentionally selecting a weak binder concentration in the formulation and using direct compression grade excipients in the fluid bed process. This formulation design decision provided a clearer focus on drug substance distribution while the DC grade excipients ensure that blend flow is not an issue for the compression process. 

Formulation development began with establishing the solubility range and solution stability of the drug substance in the granulation solution (2.5% PVP K30 in water). A usable range can vary widely.  The solution quantity needed to deliver the target composition of drug substance in the formulation will largely determine the batch time. If solubility is poor, a large quantity of granulating solution may be needed, and consequentially a long spray time with drying periods may be necessary. This scenario predictably results in long process times. Conversely, too high a drug concentration can result in spray times too short to establish uniformity in the batch. This issue can be readily mitigated by dilution of the granulating solution.  

The formulation in Table 2 was found to result in acceptable distribution of the drug substance by content uniformity (Table 3) as calculated by the USP <905> acceptance value.  In particular, the low RSD of the results indicates good uniformity was achieved. Dissolution in Figure 1 was found to be as expected for an immediate release tablet achieving >80% release in the first 10 minutes.  

Improving solubility with lipophilic excipients in solid, oral dosage formulations

To improve solubility of a lipophilic drug substance, it is sometimes necessary to include a solubilizing excipient, some of which are oily or low-melting substances themselves. For a recent project, tocofersolan or vitamin E TPGS, was incorporated into an enteric capsule formulation via high shear wet granulation. Tocofersolan is a non-traditional excipient for solid, oral dosages and in this project a creative formulation effort was needed to include this solubilizing excipient. The tocofersolan has a melting point of approximately 38°C and is a waxy solid. Additionally, the excipient is not available as a granulated or free flowing material. Therefore, the excipient is typically added to a formulation via solubilization in a granulating solution (tocofersolan is soluble in water up to approximately 20% wt).  

For this project, the client’s pre-formulation development found that a 2:1 (wt/wt) ratio of drug substance to tocofersolan was needed to achieve the projected absorption in their clinical study.  For a typical formulation with a drug loading of 30-50%, this ratio will necessitate a high loading of the tocofersolan such that incorporation via a granulating solution would result in too high of an aqueous portion during wet granulation process. In this case, the granulation would turn into a paste-like mass and be un-processable for the downstream unit operations.  

To achieve the needed loading of the tocofersolan at ~20% loading of the granulation formulation, it was proposed to add the tocofersolan as a molten liquid and distribute the material in the dry blend of the granulation equipment prior to addition of the granulating solution. It was considered that the main diluents in the formulation would be critical to successfully incorporating the tocofersolan. Choosing excipients that were porous like spray dried mannitol or microcrystalline cellulose could provide some absorptive capacity to hold the tocofersolan and prevent re-agglomeration.  

Wet granulation trials were conducted with various ratios of microcrystalline cellulose, spray dried mannitol and lactose monohydrate using the desired 2:1 (wt/wt) ratio of drug substance. Using the granulation equipment impeller and chopper, molten tocofersolan was added via the spray port and distributed in the dry material bed. A diluent system of only microcrystalline cellulose was found to provide the best distribution and retention of the tocofersolan. Additionally, the microcrystalline cellulose formulation was able to be co-milled without re-melting or extrusion of the tocofersolan excipient. Following addition of the tocofersolan, traditional spraying in the wet granulation process was performed with a povidone granulating solution. The wet material was fluid bed dried maintaining a bed temperature below the melting point of the tocofersolan. The milled granulation was filled into enteric coated capsules to create the final drug product. The formulation is included in table 4 below and a dissolution profile (two-stage, acid to base) is shown in Figure 2.  

Enhancing solubility of drug substances through salt and polymorph screening 

Small molecule API’s often suffer from poor aqueous and biorelevant solubility, which can lead to exposure issues in preclinical and clinical studies. A variety of formulation techniques can aid in improving solubility, however direct modification of API properties through salt formation can be highly effective in improving solubility without requiring significant formulation development. Solid-state experimentation such as salt screening is generally conducted by a formulation team during preformulation work. A large majority of small molecule candidates can serve as either a free acid or free base to allow for deprotonation or protonation and subsequent bonding with a suitable counterion. Addition of a charge to a previously uncharged molecule can significantly alter solubility. Common acid and basic counterions used in pharmaceutical development are shown in Table 5. 

pKa testing should be performed on the free acid or free base prior to salt screening to allow for selection of appropriate counterions. To achieve a stable salt form, a pKa difference of >2 should be maintained between free acid/base and counterion. Once counterions are selected, salt selection can occur based on desirable solubility, crystallinity and other physical properties. In addition to an improvement in solubility, a salt form of an API can have improved thermal properties, crystallinity and display a differing hygroscopicity profile versus a free acid or base. All such properties should be considered when selecting a salt form. Note that polymorph screening should be conducted if a final salt form is selected, as salt forms have unique polymorph landscapes from a free acid or base.

Table 5.1 lists biorelevant solubility results from an API that was developed as both Free Base A and a tosylate salt form. Biorelevant solubility testing was conducted in Fed-State Simulated Intestinal Fluid (FeSSIF), Fasted-State Simulated Intestinal Fluid (FaSSIF) and phosphate buffer at 37°C. Results show significantly improved solubility with the tosylate salt form. In a separate study, Free Base B was developed as both an HCl and Maleate salt. Similarly, significantly improved solubility was seen with the HCl and Maleate salt versus the free base. In an oral solid-dose formulation, such salt forms could be considered as viable candidates to improve solubility and potential bioavailability versus free base material, assuming each has acceptable physical properties. Screening of multiple counterions can allow for additional solubility selectivity. 

Conclusion

In early-phase drug product development, the formulation strategies discussed—enhancing solubility, achieving content uniformity, and optimizing drug delivery performance—are foundational to ensuring clinical trial success. These approaches address critical challenges that can impact the efficacy, safety, and scalability of investigational products, particularly in the context of diverse patient needs and complex drug properties. By leveraging innovative techniques such as salt formation, advanced granulation processes, and the use of specialized excipients, researchers can create robust formulations that meet the stringent demands of early-phase trials, while paving the way for later-stage development.

Kyle Rowinski is a scientist in the pharmaceutics group at Cambrex Longmont. His research areas focus on preformulation screening, formulation development, and solid-state optimization of small molecule drug candidates.

Matthew Haynes is the manager of the drug product formulation group at Cambrex Longmont. He has over twenty years’ experience in drug product development and technology transfer.