Semisolid Formulation Development: The CRO Approach

Introduction

Medicated creams and lotions are designed to be easy and pleasant for the customer to use. The development pathway can be challenging as these products are often complex mixtures with sophisticated requirements that are achieved via successful execution of a meticulous formulation program. For contract research organizations (CROs) that offer formulation development, the complexity of developing a semisolid formulation is often challenged by aggressive timelines frequently sought by the customer. Physicochemical characterization on the drug of interest is often limited or incomplete, an additional challenge in the development of an effective formulation. This white paper presents strategies which can be employed to develop a formulation more rapidly. Note

that this may not be the composition of the final formulation, but can be used to initiate proof-of-concept studies and add formulation criteria to the development process. This white paper contains two major sections: a review of the terminology and composition of major semisolid formulations and a presentation of a CRO’s approach to rapid formulation development. It aims to inform resource-limited staff at biotechnology or small pharmaceutical companies with their topical drug development needs following nomination of compounds suitable for progression into in vitro or preclinical testing. For successful dermal delivery, the drug must penetrate the stratum corneum (SC), an approximately pH 5 barrier to the epidermis or dermis layers. Often other factors associated with the disease state must be considered, such as absence or excess of SC, as with psoriasis. It is often a complex combination of excipients required to achieve delivery of the drug in a product that is pleasant to use by the consumer. The consumer experience of a topical product must be considered as a product that is unpleasant to use may risk lowering patient compliance and minimize market capture. This often drives a complex combination of excipients, each of which must be carefully and rationally selected based on expected improvements in the drug penetration or other performance criteria. In addition to dermal, semisolid products can be applied to buccal, nasal, ophthalmic, otic, rectal or vaginal tissue.

 

Terminology

There are several major categories of topical formulation categories: ointments, emulsions, gels, pastes, suppositories. Ointments are typically petrolatum-based formulation, although may be water-soluble if formulated with polyethylene glycol. An emulsion formulation is a suspension in which both phases are (immiscible) liquids; one liquid, the internal phase, is dispersed in the other, which is called the external or continuous phase. These may be oil-in-water, O/W, or water-in-oil, W/O. Emulsifying
agents are required to stabilize the formulation. Creams and lotions are examples of
emulsion formulations, which contain fully dissolved or suspended active ingredient;
creams are generally more viscous than lotions. Gels can be either aqueous- or organicbased. Generally, they are either suspensions of (small) inorganic particles or (large)
organic particles interpenetrated by a liquid. Gels tend to have greater structure than
ointments or emulsions, imparted by cross-linked matrices which comprise them.
Pastes, with large amounts of finely dispersed solid materials are some of the thickest
or stiffest semisolid formulations, whereas suppositories essentially seem as solid, so
the shape is maintained for insertion into a non-oral cavity, such as nasal or vaginal,
for more systemic exposure.

Table 1 presents components, brief definitions, and examples of components frequently
encountered in discussion and preparation of semisolid formulations.

 

The emulsifying agent warrants further discussion as this excipient type is the key to successfully combining two immiscible liquids and maintaining stability of the mixture. They

are employed not only to enable manufacturing processes but maintain the dispersed phase
in the continuous phase for the claimed shelf-life of the product. They also strongly influence rheological properties by modulating the interaction of the aqueous and oil phases.
Emulsifying agents, or surfactants, have a hydrophilic-lipophilic balance (HLB value) in
the range of 3-6 or 8-18. The desired HLB value would be selected based on O/W or W/O
composition of the formulation. HLB values are additive and the desired value can be
obtained by algebraic means; the proportion of each component’s HLB value will result in
the HLB value of the mixture. This allows combination of two or more excipients to obtain
the desired amount of surfactant required to obtain a stable emulsion. Note that other
excipients of agents have the following HLB ranges: wetting agents, 7-9; detergents, 13-16;
solubilizing agents, 15-20.

Formulations
The type of semisolid formulation selected will depend on its application site, the physicochemical properties of the drug, as well as the required physical properties of the formulation. A summary of four major semisolid formulation bases is presented in Table 2.
Research on the target product profile will also provide guidelines for the final product.
Formulation development will provide the data on which product strength, dosage form,
Table 2. Formulation Bases

 

release profile, penetration, cosmetic properties, and shelf life will be based. The formulation development process includes evaluating physico-chemical properties such as drug
concentration/recovery, purity, related substances, rheology, pH, viscosity. Table 3 presents model compositions of each formulation base identified above and summarizes broad
properties of each that can perhaps guide interest in one base over another. This a priori
selection may be based on: (1) the site of application; (2) properties of the active pharmaceutical ingredient, API, such as known solubility in hydrophobic or hydrophilic vehicles;
(3) release of API from the formulation into the applied area; (4) the need for a moisture
barrier; (5) the indication itself, as it may have marketed products with which it needs to
be competitive. Following the development and assessment of prototypes, stability and
activity of the API in the formulation will be key criteria. It must be established that excipients required to prepare the formulation and maintain stability of the composition do
not render the API inactive. Note that the analytical methods in use to this point must
also be characterized to ensure specificity for analysis of the API.

 

The CRO Approach
Having looked at the core composition of semisolid formulations, it is appropriate to
consider the utility of this information with respect to an individual drug development
program. Formulation CROs are contracted for the execution of the formulation process
itself, usually to be completed within a compressed time frame. Therefore, to successfully complete a project, it is absolutely necessary to think first about the path forward
prior to initiating experiments. A number of factors have been discussed in the
preceding section. These additional experiences and strategies can help save time
and money:
• Laboratory experience preparing a wide variety of formulation base types
• Sourcing uncommon excipients
• Scale-up experience, from small batch volumes (≤ 100mL) to ≥ 1L
• Development of analytical methods including extraction methods and HPLC-based
methods for drug concentration and purity
• Establishment of preservative efficacy in prototype formulations
• Assessment of prototype formulations in a thermal stability program
Hands-on experience with key prototypes can minimize the time required to develop a
formulation from its inception, accelerating the timeline to when the testing of the formulation containing the active pharmaceutical ingredient can be initiated. This is not a
“one size fits all” strategy, perhaps “one size fits most” is more appropriate. Additional
testing, of course, is required, such as:
• Discussions with leading dermatologists or other clinical staff regarding their needs
• Optimizing formulation properties such as rheology, pH, viscosity
• Establish that purity and activity of the API in the formulation are maintained
• Preparation and replicate execution of compounding procedure
• Dose uniformity
• Short-term accelerated stability testing
• Real-time stability testing, including control as well as conservative and
accelerated condition(s)
• Determination of preservative efficacy of API containing formulations
• Skin permeability and permeation studies (in vitro or ex in vivo)
• Additional in vitro tests based on project, drug, or indication to assess for product
efficacy and safety
• Determination of therapeutic efficacy, via both pre-clinical and clinical testing

 

Determination of Prototype Stability
In the initial stages of the SP Formulations semisolid development program, the thermal stability of a wide variety of cream and gel bases was examined. Typically, finished
products target the range pH 5-6. Therefore, prototypes were adjusted to be within this
range by the addition of sodium hydroxide or citric acid. Physico-chemical properties
such as pH, rheology and phase consistency (microscopic/visual) were examined following 6 weeks incubation at 2-8° C, ambient temperature, and 40° C. From this screening, several lead prototype formulations were identified (Table 4).
Determination of Preservative Efficacy
Table 4. SP Formulations Lead Formulation Prototypes

 

Optimization of preservative concentration in semi-solid formulations is a central part
of formulation development. The minimum acceptable limit of preservatives in a drug
product must be demonstrated as microbiologically effective by performing a microbial
challenge assay as specified in USP <51> as well as EP (5.1.3) and (5.1.4).
As a part of our semisolid formulation development program, the minimum effective
preservative concentrations in prototype cream and gel base formulation was established. This is especially important for the evaluation of aqueous-based gel formulations which are more susceptible to microbial growth due to their high water content.
Following study of literature and references described in the USP and EP, an optimized
set of preservatives and select concentrations were tested for the ability to arrest
microbial growth as per current regulatory requirements. All prototype oleaginous and
emulsion cream formulations passed the 28-day antimicrobial effectiveness testing at
concentrations of 0.2% w/w of benzoic acid, methylparaben and propylparaben. For the
gel formulation prototypes, a concentration of 1.5% w/w benzyl alcohol was sufficient to
prevent microbial growth over the 28-day test period.

HPLC Assay of Preservatives
During the course of any development program it is essential to validate the acceptable
preservative concentration due to labeling requirements and to account for any change
in preservative purity. To address these analytical testing needs, SP Formulations
developed robust and well-characterized extraction methods for detection of methyl and
propyl parabens and drugs such as the anti-fungal agent ketoconazole from two model
semisolid formulations: the cetyl alcohol-cetyl ester cream and the white petrolatum
cream.
Each prototype was spiked with 0.2% w/w preservative (methylparaben and propylparaben) along with 1% w/w of ketoconazole. Following a simple organic extraction test
samples were analyzed via RP-HPLC using UV detection.
The extraction method precision was determined by analyzing six replicate cream
samples prepared to contain the target amounts of each preservative and ketoconazole.
Concentrations for samples were measured by recording the appropriate peak area by
HPLC and interpreting the result according to an equation of line generated by standard
solutions for each component. The criteria for each equation of line was R-squared of at
least 0.999 and bias that was small and random for each calibration point, within ±5%.
The percent recovery value for each sample was calculated by comparing the measured
concentration with the nominal concentration; values are presented in Tables 5 and 6

Table 5. Cetyl alcohol-cetyl ester O/W cream

Table 6. White petrolatum W/O cream

The robustness of the analytical methods was characterized by extracting each spiked
agent from formulations prepared to contain 50, 100 and 150% of the target concentration. Each sample (containing the paraben preservatives and ketoconazole) were prepared and analyzed in triplicate, for a total of nine data points. The average recovery
result and relative standard deviation were as follows: methylparaben, 101.1% recovery
and 1.1% RSD; propylparaben, 99.2% recovery and 0.5 % RSD; ketoconazole, 101.2%
recovery and 0.9% RSD. The extraction method is considered suitable for a range of
excipient or active ingredient concentrations in the two cream bases examined.
To facilitate meeting regulatory requirements, stability data on pilot-scale batches
should include results from microbial challenge studies performed on the drug product
at specified intervals. This can be accomplished by analysis of preservative concentration that is known to be effective in inhibiting microbial growth. This can be done in a
manner similar to that described above or by appropriate microbiological challenge at
appropriate testing intervals. SP Formulations offers the flexibility of providing both
testing methods for preservative testing. The advantage of offering both services is the
time and cost-saving effectiveness of the analytical method, complete within 3 days,
compared to 28 days required for antimicrobial effectiveness testing. This is of particular import during the post-approval process in which production batches must be placed
on stability and demonstrate microbial effectiveness.

Conclusion
A well-characterized library of prototype formulations can be used to obviate, or at
least ameliorate, the need for lengthy ab initio semisolid formulation development.
Experience in the preparation, handling, and testing of prototype formulations is an
essential tool by which new active pharmaceutical ingredients can be incorporated into
prototypes more rapidly and subsequently tested for compatibility. Knowledge of formulation bases and properties can support the preparation of “incorporation-ready” bases
with API within several weeks. Shorter timelines may be achieved if some physicochemical characterization of the API, such as from preformulation studies on vehicle
solubility, is already complete. It is important not to rush through the necessary foundational experiments which ensure there are no unwanted drug-excipient interactions.
However, strategies like those described in this paper, may significantly reduce the time
and cost required to develop prototype formulations. This may not be the composition
of the final formulation, but can be used to initiate proof-of-concept studies and add
formulation criteria to the development process. By applying a combination of pharmaceutical development knowledge and industry experience both from executed programs
and applied research, SP Formulations can rapidly incorporate your API(s) of interest
into a suitable base(s) for initial in vitro testing such as skin penetration, permeation,
and release testing as well as in vivo efficacy testing.

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