semisolid formulation

8/4/2019 Semisolid Formulation

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W H I T E P A P E R

www.SPformulations.com

Semisolid Formulation

Development:

The CRO ApproachBy Nicole Krilla, MA, Debanjan Das, andJohn G. Augustine, PhD




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. Physico-

chemical 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 nal 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 composi-

tion 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 ratio-

nally selected based on expected improvements in the drug penetration or other per-

formance 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, emul-

sions, gels, pastes, suppositories. Ointments are typically petrolatum-based formula-

tion, although may be water-soluble if formulated with polyethylene glycol. An emul-

sion formulation is a suspension in which both phases are (immiscible) liquids; one

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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 organic-

based. 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 nely 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 denitions, and examples of components frequently

encountered in discussion and preparation of semisolid formulations.

Component Defnition Example

Antioxidant Prevents or slows oxidation of other componentsTocopherol, butylated hydroxy toluene, or a

reducing agent such as ascorbic acid

Base

Major classes or types of formulation com-

positions based on composition and physical

properties

Please refer to Table 2

Buffer

Acid-conjugate base mixture employed to control

pH and therefore control ionization state of drug

and impart stability

Citrate, phosphate, tartarate

Chelating agent

Have the ability to bind metal ions; prevents

auto-oxidation phenomena frequently catalyzed

by metal ions and enhances action of preserva-

tives by binding iron and copper ions essential

to microbial growth

EDTA, citric acid

Emuslifying agent

Reduces surface tension of two phases in an

emulsion, preventing coalescence of individual

phases

Detergent, emulsifying wax (detergent-

treated wax), cetostearyl alcohol,

polysorbate 20

Humectant Promotes retention of water in a mixtureGlycerin, propylene glycol, polyethylene

glycols (low MW)

Permeation enhancer

Faciltates diffusion process of active ingredi-

ent across the stratum corneum by chemical

modication

Ethanol, oleic acid, propylene glycol, polyeth-

ylene glycol (400)

Preservative

Prevents or slows microbial growth; may be

one of 4 major compound types: acid, alcohol,

quaternary ammonium compounds, or organic

mercurial

Acid: benzoic; alcohol: phenylethyl; quater-

nary ammonium: stearyl dimethyl benzyl

ammonium chloride; organic mercurial:

thimerosal

Thickening agentIncrease viscosity; may be natural,

semi-synthetic, or synthetic

Natural: cellulose, pectin; semi-synthetic:

methylcellulose, (sodium) carboxymethylcel-

lulose; synthetic: Carbopol

Table 1. Formulation Components

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The emulsifying agent warrants further discussion as this excipient type is the key to suc-

cessfully 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 inu-

ence 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 physico-

chemical properties of the drug, as well as the required physical properties of the formu-

lation. A summary of four major semisolid formulation bases is presented in Table 2.

Research on the target product prole will also provide guidelines for the nal product.

Formulation development will provide the data on which product strength, dosage form,

Table 2. Formulation Bases

Type Description

Oleaginous 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 sur-

face and makes removal by washing difcult.

Anhydrous 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 compo-

nents are used to introduce hydrophilic properties to the hydrophobic base.

Emulsion 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 there-

fore 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.

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release prole, penetration, cosmetic properties, and shelf life will be based. The formula-

tion development process includes evaluating physico-chemical properties such as drug

concentration/recovery, purity, related substances, rheology, pH, viscosity. Table 3 pres-

ents model compositions of each formulation base identied 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 pharma-

ceutical 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 ex-

cipients required to prepare the formulation and maintain stability of the composition donot render the API inactive. Note that the analytical methods in use to this point must

also be characterized to ensure specicity for analysis of the API.

Table 3. Base Model Compositions and Properties

Type Model Composition

Other Properties

Hydro-

phobicity

Ease of

ApplicationWashable

Incorporation

of API

Release of

API

Oleaginous

White ointment:

5% white wax95 % white petrolatum

Y Difcult N

Solid or oil-

soluble Slow

Anhydrous

Hydrophilic petrolatum:

3% cholesterol

3% stearyl alcohol

8% white wax

86% white petrolatum

Y Difcult N

Solid, oil-

soluble, or

limited aque-

ous volume

Slow

Emulsion, W/O

base

Cold cream:

12% white wax

12.5% cetyl esters wax

56% mineral oil

0.5% sodium borate

19% water

N, hydro-

philicModerate Difcult

Solid, oil-

soluble, or

limited aque-

ous volume

Moderate to

good

Emulsion, O/W

base

Hydrophilic ointment:

25% white petrolatum

25% stearyl alcohol

12% propylene glycol1% sodium lauryl sulfate

37% water

N, hydro-

philic

Moderate

or easy Y

Solid, oil-

soluble, or

limited aque-ous volume

Moderate to

good

Water-Soluble

Polyethylene Glycol

(PEG) Ointment:

60% PEG 400

40% PEG 3350

N, hydro-

philicEasy Y

Solid and

aqueous-

based

Good

Gel

Carbomer Gel:

22% propylene glycol

2% Carbopol 940

76% water

N, hydro-

philicEasy Y

Solid and

aqueous-

based

Good

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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 success-

fully complete a project, it is absolutely necessary to think rst 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 efcacy 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 for-

mulation containing the active pharmaceutical ingredient can be initiated. This is not a

“one size ts all” strategy, perhaps “one size ts 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 efcacy 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

efcacy and safety

• Determination of therapeutic efcacy, via both pre-clinical and clinical testing

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Determination of Prototype Stability

In the initial stages of the SP Formulations semisolid development program, the ther-

mal stability of a wide variety of cream and gel bases was examined. Typically, nished

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 follow-

ing 6 weeks incubation at 2-8° C, ambient temperature, and 40° C. From this screen-

ing, several lead prototype formulations were identied (Table 4).

Determination of Preservative Efcacy

Table 4. SP Formulations Lead Formulation Prototypes

Base Type Formulation Prototypes

OleaginousWhite petrolatum W/O cream

Beeswax-based W/O cream

Emulsion

Liquid Parafn-PEG O/W cream

Cetyl alcohol-cetyl ester O/W cream

Cremophor-PG O/W cream

GelHydroxyethylcellulose 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 specied 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 estab-

lished. This is especially important for the evaluation of aqueous-based gel formula-

tions 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 sufcient to

prevent microbial growth over the 28-day test period.

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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 propyl-

paraben) 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 Propylparaben Ketoconazole

Individual recovery values, %

105.9 96.8 102.7

107.9 96.3 103.2

107.5 98.3 103.5

107.4 96.0 103.6

107.3 96.0 104.0

106.5 96.8 104.0

Average recovery value, % 107.1 96.7 103.5

Standard deviation 0.8 0.9 0.5

Relative standard deviation, % 0.7 0.9 0.4

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Table 6. White petrolatum W/O cream

Spiked reagent Methylparaben Propylparaben Ketoconazole

Individual recovery values, %

105.7 94.2 101.9

105.0 97.2 103.6

106.5 95.1 105.2

103.5 98.4 104.5

106.2 94.9 105.5

108.7 97.1 107.1

Average recovery value, % 105.9 96.1 103.5

Standard deviation 1.7 1.7 1.8

Relative standard deviation, % 1.6 1.7 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 concentra-

tion. Each sample (containing the paraben preservatives and ketoconazole) were pre-

pared 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 specied intervals. This can be accomplished by analysis of preservative concentra-

tion 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 exibility 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 particu-

lar import during the post-approval process in which production batches must be placed

on stability and demonstrate microbial effectiveness.

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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 formu-

lation bases and properties can support the preparation of “incorporation-ready” bases

with API within several weeks. Shorter timelines may be achieved if some physico-

chemical characterization of the API, such as from preformulation studies on vehicle

solubility, is already complete. It is important not to rush through the necessary foun-

dational experiments which ensure there are no unwanted drug-excipient interactions.

However, strategies like those described in this paper, may signicantly reduce the timeand cost required to develop prototype formulations. This may not be the composition

of the nal formulation, but can be used to initiate proof-of-concept studies and add

formulation criteria to the development process. By applying a combination of pharma-

ceutical 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 efcacy testing.

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About SP Formulations

SP Formulations, LLC, a Smithers Group Company, delivers a broad range of formula-

tion 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 Amer-

ica and Europe, with the personalized approach of a small contract research organiza-

tion. SP Formulations can work with the exibility 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 formu-

lations, including analytical and manufacturing support.

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www.SPformulations.comSP Formulations, LLC

790 Main Street

Wareham, MA 02571-1037

Phone: +1•508•273•2236

Fax: +1•508•273•0452

Email: [email protected]

© 2009 SP Formulations

All rights reserved. Printed in U.S.A. Pub 09/09

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. Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems,

8th ed. p. 2004. Lippincott Williams and Wilkins. p. 276.

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