W H I T E

P A P E R

Semisolid Formulation Development: The CRO Approach

By Nicole Krilla, MA, Debanjan Das, and John G. Augustine, PhD

www.SPformulations.com

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 CROs 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

2
www.SPformulations.com

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.

Table 1. Formulation Components

Component Antioxidant Base Definition Prevents or slows oxidation of other components Major classes or types of formulation compositions based on composition and physical properties Acid-conjugate base mixture employed to control pH and therefore control ionization state of drug and impart stability Have the ability to bind metal ions; prevents auto-oxidation phenomena frequently catalyzed by metal ions and enhances action of preservatives by binding iron and copper ions essential to microbial growth Reduces surface tension of two phases in an emulsion, preventing coalescence of individual phases Promotes retention of water in a mixture Faciltates diffusion process of active ingredient across the stratum corneum by chemical modification Prevents or slows microbial growth; may be one of 4 major compound types: acid, alcohol, quaternary ammonium compounds, or organic mercurial Increase viscosity; may be natural, semi-synthetic, or synthetic Example Tocopherol, butylated hydroxy toluene, or a reducing agent such as ascorbic acid Please refer to Table 2

Buffer

Citrate, phosphate, tartarate

Chelating agent

EDTA, citric acid

Emuslifying agent Humectant Permeation enhancer

Detergent, emulsifying wax (detergenttreated wax), cetostearyl alcohol, polysorbate 20 Glycerin, propylene glycol, polyethylene glycols (low MW) Ethanol, oleic acid, propylene glycol, polyethylene glycol (400) Acid: benzoic; alcohol: phenylethyl; quaternary ammonium: stearyl dimethyl benzyl ammonium chloride; organic mercurial: thimerosal Natural: cellulose, pectin; semi-synthetic: methylcellulose, (sodium) carboxymethylcellulose; synthetic: Carbopol

Preservative

Thickening agent

3
www.SPformulations.com

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 components 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.
Table 2. Formulation Bases
Type Oleaginous Description Also called hydrocarbon bases due to main components: petrolatum, white petrolatum, yellow or white ointment, or mineral oil. These bases are emollient, occlusive, and endure on the applied surface for a long time. The hydrophobic nature promotes water retention within the applied surface and makes removal by washing difficult. Also called absorption bases because of the ability to absorb water. Used pharmaceutically to incorporate an aqueous-based drug into an oleaginous base. Either the base does not contain aqueous but is capable of absorbing water to form a W/O emulsion or is a W/O emulsion to which additional small amounts of aqueous can be introduced. Lanolin, cholesterol, or other components are used to introduce hydrophilic properties to the hydrophobic base. Emulsion bases may be W/O or O/W. W/O, water in oil, emulsions are emollient, occlusive, may feel greasy, and hard to wash off. Typically composed of an oleaginous base + water (<45%) + surfactant with HLB 8. O/W, oil in water, emulsions are not occlusive, do not feel greasy, are water-washable, and therefore not as emollient. O/W emulsion base formulations can be used to absorb watery discharge. Typically composed of an oleaginous base + water (>45%) + surfactant with HLB 9 Water-Soluble Majority are polyethylene glycol-based. Not occlusive, not greasy, and water-washable. A gel would be a type of water-soluble base.

Anhydrous

Emulsion

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,

4
www.SPformulations.com

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.

Table 3. Base Model Compositions and Properties

Other Properties Type Model Composition White ointment: 5% white wax 95 % white petrolatum Hydrophilic petrolatum: 3% cholesterol 3% stearyl alcohol 8% white wax 86% white petrolatum Cold cream: 12% white wax 12.5% cetyl esters wax 56% mineral oil 0.5% sodium borate 19% water Hydrophilic ointment: 25% white petrolatum 25% stearyl alcohol 12% propylene glycol 1% sodium lauryl sulfate 37% water Polyethylene Glycol (PEG) Ointment: 60% PEG 400 40% PEG 3350 Carbomer Gel: 22% propylene glycol 2% Carbopol 940 76% water Hydrophobicity Y Ease of Application Difficult Washable N Incorporation of API Solid or oilsoluble Solid, oilsoluble, or limited aqueous volume Solid, oilsoluble, or limited aqueous volume Release of API Slow

Oleaginous

Anhydrous

Difficult

Slow

Emulsion, W/O base

N, hydrophilic

Moderate

Difficult

Moderate to good

Emulsion, O/W base

N, hydrophilic

Moderate or easy

Solid, oilsoluble, or limited aqueous volume Solid and aqueousbased Solid and aqueousbased

Moderate to good

Water-Soluble

N, hydrophilic

Easy

Good

Gel

N, hydrophilic

Easy

Good

5
www.SPformulations.com

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

6
www.SPformulations.com

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 Base Type Oleaginous Emulsion Gel Formulation Prototypes White petrolatum W/O cream Beeswax-based W/O cream Liquid Paraffin-PEG O/W cream Cetyl alcohol-cetyl ester O/W cream Cremophor-PG O/W cream Hydroxyethylcellulose gel Carbopol gel

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.

7
www.SPformulations.com

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 Spiked reagent Methylparaben 105.9 107.9 Individual recovery values, % 107.5 107.4 107.3 106.5 Average recovery value, % Standard deviation Relative standard deviation, % 107.1 0.8 0.7 Propylparaben 96.8 96.3 98.3 96.0 96.0 96.8 96.7 0.9 0.9 Ketoconazole 102.7 103.2 103.5 103.6 104.0 104.0 103.5 0.5 0.4

8
www.SPformulations.com

Table 6. White petrolatum W/O cream Spiked reagent Methylparaben 105.7 105.0 Individual recovery values, % 106.5 103.5 106.2 108.7 Average recovery value, % Standard deviation Relative standard deviation, % 105.9 1.7 1.6 Propylparaben 94.2 97.2 95.1 98.4 94.9 97.1 96.1 1.7 1.7 Ketoconazole 101.9 103.6 105.2 104.5 105.5 107.1 103.5 1.8 1.7

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.

9
www.SPformulations.com

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.

10
www.SPformulations.com

About SP Formulations
SP Formulations, LLC, a Smithers Group Company, delivers a broad range of formulation services for small and large molecules in a variety of pharmaceutical dosage forms including liquids, solids and semi-solids. As a member company of the internationally recognized research and testing leader, The Smithers Group, SP Formulations has unique abilities to support pre-clinical and clinical drug development for North America and Europe, with the personalized approach of a small contract research organization. SP Formulations can work with the flexibility of an R&D organization or under the greater rigor of a regulated environment to meet different program stage needs. SP Formulations offers a full-service package for pre-clinical and clinical drug formulations, including analytical and manufacturing support.

11
www.SPformulations.com

References
1. Davies, JT. Proc Int Congress of Surface Activity (1957): pp. 426-438. 2. Swarbrick, J. Encyclopedia of Pharmaceutical Technology, 3rd ed. 1996. Marcel Deckker Inc. p. 3257. 3. Chater, SJ. Cooper and Gunn Dispensing For Pharmaceutical Students, 12th ed. 2001. CBS Publication. pp. 192-231. 4. Gennaro, RA. Remington: The Science and Practice of Pharmacy, 19th ed. 1995. Mack publishing Company. pp. 304-310. 5. Aulton, ME. Pharmaceutics the Science of Dosage Form Design, 1st ed. 1988. Churchill Livingstone. p. 386. 6. Allen, LV, et al. Ansels Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th ed. p. 2004. Lippincott Williams and Wilkins. p. 276.

www.SPformulations.com
SP Formulations, LLC 790 Main Street Wareham, MA 02571-1037 Phone: +15082732236 Fax: +15082730452 Email: info@spformulations.com
2009 SP Formulations All rights reserved. Printed in U.S.A. Pub 09/09

12
www.SPformulations.com