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P A P E R
Semisolid Formulation Development: The CRO Approach
By Nicole Krilla, MA, Debanjan Das, and John G. Augustine, PhD
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. otic. nasal. 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. emulsions. gels. although may be water-soluble if formulated with polyethylene glycol. This often drives a complex combination of excipients. the drug must penetrate the stratum corneum (SC). as with psoriasis. Note that this may not be the composition of the final formulation. Terminology There are several major categories of topical formulation categories: ointments. an additional challenge in the development of an effective formulation. pastes. ophthalmic.SPformulations. Physicochemical characterization on the drug of interest is often limited or incomplete. Ointments are typically petrolatum-based formulation. rectal or vaginal tissue.com . suppositories. 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. Often other factors associated with the disease state must be considered. an approximately pH 5 barrier to the epidermis or dermis layers. one 2 www. such as absence or excess of SC. For successful dermal delivery. 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. semisolid products can be applied to buccal. each of which must be carefully and rationally selected based on expected improvements in the drug penetration or other performance criteria. 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. An emulsion formulation is a suspension in which both phases are (immiscible) liquids. In addition to dermal.Introduction Medicated creams and lotions are designed to be easy and pleasant for the customer to use. This white paper presents strategies which can be employed to develop a formulation more rapidly. the complexity of developing a semisolid formulation is often challenged by aggressive timelines frequently sought by the customer. but can be used to initiate proof-of-concept studies and add formulation criteria to the development process. For contract research organizations (CROs) that offer formulation development.
quaternary ammonium compounds. Gels tend to have greater structure than ointments or emulsions. polysorbate 20 Glycerin. phosphate. Emulsifying agents are required to stabilize the formulation.or organicbased. cetostearyl alcohol. W/O. imparted by cross-linked matrices which comprise them. quaternary ammonium: stearyl dimethyl benzyl ammonium chloride. organic mercurial: thimerosal Natural: cellulose. synthetic: Carbopol Preservative Thickening agent 3 www. 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. which contain fully dissolved or suspended active ingredient. polyethylene glycols (low MW) Ethanol. semi-synthetic: methylcellulose. (sodium) carboxymethylcellulose.liquid. These may be oil-in-water. whereas suppositories essentially seem as solid. or a reducing agent such as ascorbic acid Please refer to Table 2 Buffer Citrate. Pastes. semi-synthetic.SPformulations. so the shape is maintained for insertion into a non-oral cavity. 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. the internal phase. which is called the external or continuous phase. alcohol: phenylethyl. for more systemic exposure. with large amounts of finely dispersed solid materials are some of the thickest or stiffest semisolid formulations. Table 1. butylated hydroxy toluene. such as nasal or vaginal. tartarate Chelating agent EDTA. brief definitions. Gels can be either aqueous. citric acid Emuslifying agent Humectant Permeation enhancer Detergent. or water-in-oil. may be one of 4 major compound types: acid. oleic acid. Table 1 presents components. pectin.com . may be natural. propylene glycol. emulsifying wax (detergenttreated wax). is dispersed in the other. O/W. polyethylene glycol (400) Acid: benzoic. or organic mercurial Increase viscosity. Creams and lotions are examples of emulsion formulations. alcohol. they are either suspensions of (small) inorganic particles or (large) organic particles interpenetrated by a liquid. and examples of components frequently encountered in discussion and preparation of semisolid formulations. 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. Generally. or synthetic Example Tocopherol. creams are generally more viscous than lotions. propylene glycol.
They also strongly influence rheological properties by modulating the interaction of the aqueous and oil phases. Typically composed of an oleaginous base + water (>45%) + surfactant with HLB ≥ 9 Water-Soluble Majority are polyethylene glycol-based. Also called absorption bases because of the ability to absorb water. and hard to wash off. water in oil. 7-9. occlusive. Emulsifying agents. do not feel greasy. Note that other excipients of agents have the following HLB ranges: wetting agents. occlusive. W/O. The hydrophobic nature promotes water retention within the applied surface and makes removal by washing difficult. 4 www. This allows combination of two or more excipients to obtain the desired amount of surfactant required to obtain a stable emulsion. Lanolin. the physicochemical properties of the drug. dosage form. Formulation development will provide the data on which product strength.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. Formulations The type of semisolid formulation selected will depend on its application site. Table 2. Used pharmaceutically to incorporate an aqueous-based drug into an oleaginous base. the proportion of each component’s HLB value will result in the HLB value of the mixture. O/W emulsion base formulations can be used to absorb watery discharge. cholesterol. emulsions are not occlusive. Typically composed of an oleaginous base + water (<45%) + surfactant with HLB ≤ 8. 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. A gel would be a type of water-soluble base. white petrolatum. Formulation Bases Type Oleaginous Description Also called hydrocarbon bases due to main components: petrolatum. are water-washable. as well as the required physical properties of the formulation. and water-washable. may feel greasy. or mineral oil. The desired HLB value would be selected based on O/W or W/O composition of the formulation. 13-16. detergents. and endure on the applied surface for a long time. A summary of four major semisolid formulation bases is presented in Table 2. solubilizing agents. Emulsion bases may be W/O or O/W. These bases are emollient. or surfactants. or other components are used to introduce hydrophilic properties to the hydrophobic base. Anhydrous Emulsion Research on the target product profile will also provide guidelines for the final product. oil in water.com .SPformulations. HLB values are additive and the desired value can be obtained by algebraic means. O/W. 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. and therefore not as emollient. not greasy. 15-20. emulsions are emollient. Not occlusive. have a hydrophilic-lipophilic balance (HLB value) in the range of 3-6 or 8-18. yellow or white ointment.
Table 3. viscosity. hydrophilic Easy Y Good 5 www. or limited aqueous volume Solid. or limited aqueous volume Solid and aqueousbased Solid and aqueousbased Moderate to good Water-Soluble N. Note that the analytical methods in use to this point must also be characterized to ensure specificity for analysis of the API. penetration. stability and activity of the API in the formulation will be key criteria.com . oilsoluble. The formulation development process includes evaluating physico-chemical properties such as drug concentration/recovery. hydrophilic Moderate or easy Y Solid. (5) the indication itself.SPformulations. or limited aqueous volume Release of API Slow Oleaginous Anhydrous Y Difficult N Slow Emulsion. and shelf life will be based. related substances. cosmetic properties. O/W base N. hydrophilic Easy Y Good Gel N. This a priori selection may be based on: (1) the site of application. (3) release of API from the formulation into the applied area. oilsoluble.5% cetyl esters wax 56% mineral oil 0. 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. 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. such as known solubility in hydrophobic or hydrophilic vehicles. rheology. as it may have marketed products with which it needs to be competitive. (4) the need for a moisture barrier.release profile.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. It must be established that excipients required to prepare the formulation and maintain stability of the composition do not render the API inactive. oilsoluble. W/O base N. API. purity. Following the development and assessment of prototypes. hydrophilic Moderate Difficult Moderate to good Emulsion. (2) properties of the active pharmaceutical ingredient. pH.
to successfully complete a project.com . accelerating the timeline to when the testing of the formulation containing the active pharmaceutical ingredient can be initiated. Therefore. or indication to assess for product efficacy and safety • Determination of therapeutic efficacy.SPformulations. it is appropriate to consider the utility of this information with respect to an individual drug development program. drug. Formulation CROs are contracted for the execution of the formulation process itself. 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. perhaps “one size fits most” is more appropriate. such as: • Discussions with leading dermatologists or other clinical staff regarding their needs • Optimizing formulation properties such as rheology. of course. usually to be completed within a compressed time frame.The CRO Approach Having looked at the core composition of semisolid formulations. Additional testing. 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. via both pre-clinical and clinical testing 6 www. 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. This is not a “one size fits all” strategy. 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. pH. is required. 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.
Following study of literature and references described in the USP and EP. For the gel formulation prototypes. Typically. the minimum effective preservative concentrations in prototype cream and gel base formulation was established. prototypes were adjusted to be within this range by the addition of sodium hydroxide or citric acid. 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 thermal stability of a wide variety of cream and gel bases was examined. a concentration of 1.3) and (5. Therefore. Physico-chemical properties such as pH. rheology and phase consistency (microscopic/visual) were examined following 6 weeks incubation at 2-8° C. several lead prototype formulations were identified (Table 4). 7 www. 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.Determination of Prototype Stability In the initial stages of the SP Formulations semisolid development program. As a part of our semisolid formulation development program. All prototype oleaginous and emulsion cream formulations passed the 28-day antimicrobial effectiveness testing at concentrations of 0. finished products target the range pH 5-6.4). From this screening.1.1.2% w/w of benzoic acid. an optimized set of preservatives and select concentrations were tested for the ability to arrest microbial growth as per current regulatory requirements.5% w/w benzyl alcohol was sufficient to prevent microbial growth over the 28-day test period. methylparaben and propylparaben.SPformulations. and 40° C. 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. ambient temperature.com . Determination of Preservative Efficacy Table 4.
9 Ketoconazole 102. To address these analytical testing needs.7 0.6 104.8 96.5 Average recovery value.1 0. The criteria for each equation of line was R-squared of at least 0.2 103.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.9 0.8 96.5 0. 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. within ±5%.0 96.0 96. Following a simple organic extraction test samples were analyzed via RP-HPLC using UV detection.3 98.999 and bias that was small and random for each calibration point. Cetyl alcohol-cetyl ester O/W cream Spiked reagent Methylparaben 105. The extraction method precision was determined by analyzing six replicate cream samples prepared to contain the target amounts of each preservative and ketoconazole.9 107.9 Individual recovery values. % 107. Each prototype was spiked with 0.com .2% w/w preservative (methylparaben and propylparaben) along with 1% w/w of 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.4 8 www. % 107. Table 5.7 Propylparaben 96.4 107.0 104.5 0.3 96.SPformulations.7 103. % Standard deviation Relative standard deviation.5 103.0 103. values are presented in Tables 5 and 6.3 106.5 107. The percent recovery value for each sample was calculated by comparing the measured concentration with the nominal concentration.8 0.
2 104.1% recovery and 1. This is of particular import during the post-approval process in which production batches must be placed on stability and demonstrate microbial effectiveness. stability data on pilot-scale batches should include results from microbial challenge studies performed on the drug product at specified intervals.1 98.5 107. Each sample (containing the paraben preservatives and ketoconazole) were prepared and analyzed in triplicate. 9 www.2 97.Table 6. compared to 28 days required for antimicrobial effectiveness testing. The extraction method is considered suitable for a range of excipient or active ingredient concentrations in the two cream bases examined.1 1. complete within 3 days. SP Formulations offers the flexibility of providing both testing methods for preservative testing. ketoconazole.9 1. The average recovery result and relative standard deviation were as follows: methylparaben.2 95.7 Average recovery value.7 Ketoconazole 101.9% RSD.7 105.8 1. 101. White petrolatum W/O cream Spiked reagent Methylparaben 105.1 96. % 105.5 103.5 1.7 The robustness of the analytical methods was characterized by extracting each spiked agent from formulations prepared to contain 50. This can be accomplished by analysis of preservative concentration that is known to be effective in inhibiting microbial growth.6 105.7 1.2% recovery and 0. propylparaben.5 % RSD.9 103.5 105.7 1. % Standard deviation Relative standard deviation. 101.SPformulations. % 106.2% recovery and 0. 99. This can be done in a manner similar to that described above or by appropriate microbiological challenge at appropriate testing intervals.0 Individual recovery values. To facilitate meeting regulatory requirements. 100 and 150% of the target concentration.4 94.5 106.com .1 103. The advantage of offering both services is the time and cost-saving effectiveness of the analytical method.9 97.2 108.6 Propylparaben 94. for a total of nine data points.1% RSD.
and release testing as well as in vivo efficacy testing. By applying a combination of pharmaceutical development knowledge and industry experience both from executed programs and applied research. 10 www. It is important not to rush through the necessary foundational experiments which ensure there are no unwanted drug-excipient interactions. handling. may significantly reduce the time and cost required to develop prototype formulations. the need for lengthy ab initio semisolid formulation development. This may not be the composition of the final formulation.com . SP Formulations can rapidly incorporate your API(s) of interest into a suitable base(s) for initial in vitro testing such as skin penetration. is already complete. Experience in the preparation. permeation. or at least ameliorate. However. strategies like those described in this paper. 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. such as from preformulation studies on vehicle solubility. Knowledge of formulation bases and properties can support the preparation of “incorporation-ready” bases with API within several weeks.SPformulations. Shorter timelines may be achieved if some physicochemical characterization of the API.Conclusion A well-characterized library of prototype formulations can be used to obviate. but can be used to initiate proof-of-concept studies and add formulation criteria to the development process.
The Smithers Group. SP Formulations offers a full-service package for pre-clinical and clinical drug formulations. solids and semi-solids.SPformulations.About SP Formulations SP Formulations.com . including analytical and manufacturing support. 11 www. As a member company of the internationally recognized research and testing leader. 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. 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. SP Formulations has unique abilities to support pre-clinical and clinical drug development for North America and Europe. LLC. with the personalized approach of a small contract research organization.
Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. 2004. 2. Swarbrick. 1st ed. Printed in U. MA 02571-1037 Phone: +1•508•273•2236 Fax: +1•508•273•0452 Email: info@spformulations. Pharmaceutics the Science of Dosage Form Design. 276. Remington: The Science and Practice of Pharmacy. 3rd ed. 1988. 386. RA.S. CBS Publication. 426-438. J. p. 5. Mack publishing Company. Aulton. 19th ed. Lippincott Williams and Wilkins. Encyclopedia of Pharmaceutical Technology. 3257.SPformulations. 1995.References 1. 12th ed.com SP Formulations. Davies. p. Cooper and Gunn Dispensing For Pharmaceutical Students. pp. 304-310. p.A. Proc Int Congress of Surface Activity (1957): pp. Chater. p. JT. 8th ed. Churchill Livingstone. LLC 790 Main Street Wareham. 4. Allen. Gennaro. 3. 192-231. pp. 1996. LV. 2001.com © 2009 SP Formulations All rights reserved. Marcel Deckker Inc. Pub 09/09 12 www. SJ.com . ME. www.SPformulations. 6. et al.
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