3/7/13

LECTURE 10 FORMULATION CHEMISTRY SHORT TEST (Formulation) March 12

FINALS Tues., March 19, 9:30-11:30, C114

FORMULATION CHEMISTRY FORMULATION CHEMISTRY

n Formulation chemistry is the mixing of compounds/ substances that do not react with each other but n Many modern products contain a combination of several produce a mixture with the desired characteristics/ chemical substances, each contributing an advantage to properties to suit a particular application/use. the finished product for a particular application.

1 3/7/13

FORMULATION CHEMISTRY FORMULATION CHEMISTRY n Any developed product must be commercially viable i.e. a n Since no reactions happen in making the mixture, most useful profitable material, so, almost every example quoted formulations are prepared by measuring liquids by volume and below, you will actually find in your home i.e. a broad range of solids by mass ('weight'). It is perfectly possible for a marketed useful household products are the result of the science of product to go on sale without a chemical equation ever being formulation chemistry. written down!

FORMULATION CHEMISTRY

n Although there are no chemical reactions involved in n However, there may be much chemistry going on to actually preparing formulations, there are many chemical make some of the ingredients e.g. chemically synthesising a aspects to do with formulation. These include drug is one matter, mixing it with water and other ingredients thermodynamics (energy changes) of mixing, phase to make a liquid medicine for oral consumption is another! equilibria, solutions, surface chemistry, colloids, emulsions and suspensions.

2 3/7/13

FORMULATION CHEMISTRY FORMULATION CHEMISTRY

n These important principles and ingredients may be n By changing the composition of the mixture, its related to properties such as adhesion, weather properties will change to be more or less suited to a resistance, texture, shelf-life, biodegradability, particular useful application. Quite a bit of trial and error allergenic response and many other properties. goes into product formulation research and even computer programes have been developed to model and therefore predict the properties a mixture may have - BUT its still got to be tested in the laboratory.

EXAMPLES - PAINTS EXAMPLES - PAINTS

n A paint is made up of a base pigment, a mixture of n Binders bind the pigment to the surface painted and compounds to give it a particular color, a binder and a pigments must be insoluble materials e.g. titanium solvent which evaporates to give a hard solid surface dioxide and zinc oxide are used as white pigments (and finish (matt or gloss depending on the composition). have replaced potentially harmful lead pigments). Paints may be water, latex, oil, acrylic or epoxy based. Sometimes the binding action involves a chemical House paints must be reasonably durable at a change e.g. polymerisation. Acrylic paints use polymer reasonable price but high durability paints used for car resins as a solvent and can be thinned with water, but and aircraft bodies are more costly. still dry easily.

3 3/7/13

EXAMPLES – INKS and DYES EXAMPLES – INKS and DYES

There is a huge variety of inks available of different Good color quality is required for glossy magazines. As well compositions to suit different circumstances. Ink used for as colour composition, appropriate ink flow is important newspapers or paperback novels must be cheap and have for pens and computer printers. The performance and the consistency of a thick sludge to properly feed through formulation of a good photocopier or laser printer toner the ink rollers of a printing press. depends upon its electrostatic properties.

COSMETICS AND OTHER 'PERSONAL PRODUCTS' OTHER EXAMPLES

n The cosmetic industry provides a wide range of Petrolium Oil Products, Detergents (gels, formulated products. In the bathroom/bedroom you may find perfumes, moisturizers, lipstick, antiaging skin bars, liquids, granules), Soap (blocks/ products, face powder, nail polish, sunscreen/ powders, liquids), Perfumes and Flavors, sunblocker, hair gel, hair conditioning and colouring Pharmaceutical products, adhesives, products, aftershave and deodorants etc. pesticides, Food industry products, dietary supplements.

4 3/7/13

What form? What form?

Consumer preferred Solid (granular, block), encapsulated solids Ease of formulation Gels and Paste Cost. Liquids (solutions, emulsions) (dispersions) (dilute or concentrated)

MODE OF USE/DELIVERY PRODUCT AESTHETICS

- direct application - odor, flavor

- dilute and use - Color

- - Spray-on - Form

- With implements (tooth brush, foam) - others

5

MANUFACTURING IN COSMETICS

FROM THE LABORATORY TO 3/7/13 FULL PRODUCTION

PRIMARY AND SECONDARY BENEFITS

Two in one shampoo Detergents for cleaning but can claim antibacterial benefit. Dishwashing with glass repair

Emulsion Chemistry Emulsion Chemistry OUTLINE – WHAT YOU SHOULD LEARN

n Learn about emulsions Cosmetic Formulation n What they are n Where they are used n How you make them n Practical information

23 24

6 3/7/13

Emulsion Chemistry: Emulsion Chemistry: Cosmetics The Problem - OILS

n Oils are excellent cosmetic materials n Cosmetics are all about changing / n Improve surface feel improving surfaces n Protect n Aid in moisturization n Reduce static n Shine n Don’t wash away n Oils have drawbacks n Tacky, greasy 25 26 n Cost too much

Emulsion Chemistry: Emulsion Chemistry: The Solution – Dilution! The Problem

n Oil & Water Do Not Stay Mixed n Why?

n Lower free energy when separate n Why?

n Hydrogen Bonding

n Oils are non-polar

n Size of molecules

27 28

7 3/7/13

Emulsion Chemistry: Emulsion Chemistry The Solution Emulsifier – The Stabilizer

n Add energy to the system n Lipophilic tails & Hydrophilic heads n Agitation

n Heat n Need something to stabilize  Reduce interfacial surface tension n Surfactants or Emulsifiers  Helps disperse oil in water  29 Forms micelles in solution 30

Emulsion Chemistry: Emulsion Chemistry: Micelle formation The Solution

n Oil breaks into tiny droplets (particles) Molecules in Motion

n Hydrophilic heads align with water

n Lipophilic tails

align with oil 31 32

n Note: More structures than this formed in solution. Depends on surfactant concentration

8 3/7/13

Emulsion! Common Emulsions

Peanut Butter 33 Milk Salad Dressing 34

Emulsion Chemistry Emulsion Chemistry EMULSIONS EMULSIONS n Pseudo-Stable mixtures of oils & water n Why are they useful? n Three phases n Improved feel

n Internal Phase n Easier to apply – Shear thinning

n External Phase n Less chemical exposure = safer

n Emulsifier n Use the right amount n It’s generally cheaper!

35 36

9 3/7/13

Emulsion Chemistry Emulsion Chemistry EMULSIONS - PARTICLES Emulsions – Particle Size n The importance of particle size Type Particle Size

n Clarity Macroemulsion >1000 nm n Stability Microemulsion 10 – 300 nm n Characterization Micelles 5 – 10 nm n Macroemulsions Solutions <5 nm n Microemulsions (also Nanoemulsions) 37 38

Emulsion Chemistry Emulsion Chemistry EMULSIONS - TYPES Oil in Water – O/W n Type of emulsions n Internal phase = oil

n Oil in Water n External phase = water

n Water in Oil n Advantages

n n Multiple emulsions Easiest to formulate n Least expensive

n Best feel – cooling effect n Disadvantages 39 40 n Less oil delivered

n Not as effective for dry skin

n Not water-resistant

10 3/7/13

Emulsion Chemistry Example Product – O/W Water in Oil – W/O

n Internal phase = water St. Ives Vitamin E Lotion n External phase = oil

Water (Aqua), Glycerin, Mineral Oil (Paraffinum Liquidum), Stearic n Advantages Acid, Glycol Stearate, Stearamide AMP, Petrolatum, Dimethicone, n Waterproofing possible Tocopherol, Tocopheryl Acetate, Chamomilla Recutita Flower Extract (Matricaria), Helianthus Annuus Extract (Sunflower), Sambucus n Most effective for dry skin Nigra Flower Extract, Primula Veris Extract, Theobroma Cacao Seed n Better stability Butter (Cocoa), Glyceryl Stearate, Cetyl Alcohol, Triethanolamine, Other Products Acetylated Lanolin Alcohol, Cetyl Acetate, Magnesium Aluminum n Disadvantages Hair conditioners Silicate, Carbomer, Propylene Glycol, Propylparaben, Methylparaben, Sunscreen n Oily, tacky feel Wrinkle Creams DMDM Hydantoin, Disodium EDTA, Sorbitol, Fragrance (Parfum), Yellow 5 (CI 19140) n More expensive 41 42

Emulsion Chemistry Example Product – W/O Emulsions – Differences

Philosophy hope in a tube, Firming cream Water (aqua), Squalane, Mineral Oil, Glycerin, Isocetyl n Is it O/W or W/O? Stearoyl Stearate, Petrolatum, Butylene Glycol, Polyglyceryl 2 Diisostearate, PEG 30 Dipolyhydroxystearate, Ceresin, n Dilution – O/W disperses more easily Polyethylene, Microcrystalline Wax, Magnesium Sulfate, Phytosteryl/Octyldodecyl/Lauroyl Glutamate, Dipalmitoyl n pH – O/W has consistent pH Hydroxyproline, Tocopheryl Acetate, Polysorbate 80, Bisabolol, Potassium Ascorbyl Tocopheryl Phosphate, Iron n Conductivity – O/W conducts electricity Oxide (CI 77492, CI 77491 and CI77499), Methylparaben, Diazolidinyl Urea, Ethylparaben, Tetrasodium EDTA

43 44

11 3/7/13

Emulsion Chemistry Multiple Emulsions EMULSION STABILITY

n Multiple phases

n Oil in Water in Oil (O/W/O)

n Water in Oil in Water (W/O/W) n Advantages

n More effective than Oil in Water

n Less greasy than Water in oil

n Time release, active delivery possible n Disadvantages

n Hard to manufacture 45 46 n Not always stable

Emulsion Chemistry Emulsion Chemistry: Emulsion - Stability Emulsions - Stability Problems

n Emulsions are inherently unstable

n Second Law of Thermodynamics  Flocculation  Coalescence  n Good emulsions last a long time Creaming  Inversion

n But eventually, these things happen… 47 48

12 3/7/13

Emulsion Chemistry Emulsion – Stability EMULSION FORMULATION n Formulators fight the Second Law! n Prolong the life of the product n How?

n Emulsifiers

n Thickeners

n Particle Size n Testing for stability

n Viscosity Checks

n Appearance 49 50

Emulsion Chemistry: Emulsion Chemistry: ELEMENTS OF THE FORMULA Emulsions – Oil Phase

n Formula Components n Examples in cosmetics

n Oil Phase n Lanolin and derivatives

n Hydrophobic materials n Natural Oils / Fats

n Oils, esters, fragrances n Waxes

n Aqueous phase n Silicones

n Extracts, colorants n Esters

n Humectants n Emollients (moisturizers) n Thickeners n Emulsifiers 51 52 n Holds it all together

13 3/7/13

Emulsion Chemistry: Emulsion Chemistry: Emulsions – Aqueous Phase Emulsions – Aqueous Phase

n Anything that is soluble in water n Thickeners to stabilize the emulsion n Examples in cosmetics n Examples in cosmetics

n Water n Carbomer

n Hydrolyzed proteins n Locust bean gum

n Humectants n Xanthan gum

n Glycols n Cellulosics

n Extracts n PVP/Decene copolymer

n Dyes

n Polymers, thickeners 53 54 n Acids, etc.

Emulsion Chemistry: Emulsion Chemistry: Emulsions – Emulsifiers Typical Emulsifiers

n Surfactants n Glyceryl Stearate n Anionic n Carboxylic acids : Soaps n PEG-100 Stearate n Sulfonic acids: Sulfosuccinate esters n Stearyl Alcohol n Cationic n Amines : PEG Alkyl amine n Cetyl Alcohol n Quaternaries: Tetraalkyl ammonium salts n Laureth-23 n Amphoterics Most common n n Steareth Alcohol Phospholipids For Cosmetic n Nonionics Emulsions n Cetyl/PEG/PPG 10 Dimethicone n Fatty Alcohols 55 n 56 n Esters Stearic Acid n Polymers

14 3/7/13

Emulsion Chemistry: Emulsifiers – HLB Emulsions – HLB HYDROPHOBE/LIPOPHOBE BALANCE

n How to pick emulsifiers n Varying degrees of non-polar & polar character.

n Mostly, it’s trial and error

Less polar (low HLB) n Modify starting formulas

n Or Learn to use HLB More Polar (High HLB)

n Specific oils need specific surfactant polar/non-polar character to be effectively emulsified. 57 58

Emulsion Chemistry: Emulsion Formulation: HLB System Emulsions – HLB

n HLB system - n William Griffin from Uniqema in 1949 n System to quickly create stable emulsions n Works best with nonionic surfactants n Ingredients are assigned an HLB value

n(based on molecular weight & solubility) n Lower values are less water soluble n Oils are assigned HLB values n Amount of emulsifier is calculated Common Oils used and the HLB needed to Create an emulsion

59 60

15 3/7/13

Emulsion Chemistry: Emulsion Chemistry: Emulsions – HLB Emulsions – HLB Formula

Chemical Ethylene Glycol Glyceryl Stearate Sorbitan Palmitate Laureth-4 Nonoxynol-9 Polysorbate-80 • HLB is only a good approximation • Doesn’t always work

• Multiple emulsifiers improve stability • More emulsifier is used than needed 61 62

Emulsion Chemistry: EMULSIONS – MAKING THEM Simple Oil In Water Emulsion

n Typical Formulation

n Oil and Water Phase are mixed separately

n Oil phase is heated

n to melt waxes & fatty alcohols

n Mixed with surfactants

n Cooled while being agitated

n this makes the appropriate particle size 63 64

16 3/7/13

Simple Water in Oil Emulsion Simple Micro Emulsion

65 66

Actual Formulation!! Emulsion Making: Scale up

Pilot Plant Equipment

67 68

17 3/7/13

Emulsion Chemistry: Emulsion Chemistry: Emulsions – Summary Emulsions – Where to learn more

n n Emulsion defined Starting Formulas n happi.com n Emulsification by surfactants n Allured.com n Types of Emulsions n Harry’s Cosmeticology n Emulsion stability n Rieger: Chemical Publishing co n HLB n Handbook of Cosmetic Science & Technology n Maibach: Marcel Dekker n Emulsion formulation n The Chemistry & Manufacture of Cosmetics n Schlossman: Allured Publishing 69 70

n TYPES OF COSMETIC PRODUCT FORMS COSMETIC PRODUCT FORMS

n COSMETIC R&D LABORATORY & EQUIPMENT FOR n Selection of a proper product form is important in order to achieve FORMULA PREPARATION. the criteria of marketing and technical attributes desired in the final system. n STABILITY & TESTING PARAMETERS. n One must balance the desired consumer perceived benefits with the technical ability in the formula to deliver such benefits. n PILOT SCALEUP OF COSMETIC FORMULATIONS AND ASSOCIATED PARAMETERS.

n MANUFACTURING IN THE PLANT ENVIRONMENT

18 3/7/13

SOLUTIONS SOLUTIONS

n These are the simplest forms of cosmetic products. Are n In most cases heating and/or cooling are not required to achieve a characterized as liquid systems in which all of the constituents are homogenous solution ; the only thing needed is adequate mixing of soluble. the components. n Solutions can be water or oil based systems and are easy to manufacture as they usually consist of utilizing a single mixing n Even though solutions are easy to produce from a manufacturing vessel where the main diluents is added and then mixing in one perspective, they do possess the downside of offering little ingredient after another. functionality. Many functional cosmetic ingredients have limited or no solubility in water and require other product forms.

CREAMS CREAMS

n Most cosmetic cream formulations are emulsions which are defined as a heterogeneous system composed of an immiscible liquid n Most (75 % +) of cosmetic creams are of the OIL-IN-WATER type dispersed as droplets in another liquid. with an oil phase ranging from 10%-25%. Typical products that use creams are Shaving products , Skin care, Antiperspirants, etc. n Emulsified cream products can be O/W or W/O systems depending n Most cream formulations of cosmetic products are well perceived on the continuous phase. by the consumer and have aesthetic appeal.

n However, since this dosage form is an emulsion they are inherently unstable and proper stability testing must be done in the lab before releasing for actual manufacturing on a large scale.

19 3/7/13

LOTIONS LOTIONS

n From a manufacturing perspective lotions are easier to produce as n This is the type of product form that is used in applications, where a they are less viscous and heating and cooling times are lessened. less viscous dosage form is desired from a rheological perspective. n From a rheological perspective, it is important to remember that They can be defined as thin creams. lotions are less stable thermodynamically from creams because the higher viscosity of a cream will slow down the natural destabilizing n As these products are also emulsions in nature they are less greasy forces. to the touch and are lighter in texture to the consumer. n Examples of products that utilize the lotion form are : n Skin and Facial Lotions n Hair Conditioners n Moisturizing Cleansers

OINTMENTS AND PASTES OINTMENTS AND PASTES

n It is important to note that since this product form are essentially n This type of product form is utilized when there is a desire for a oil based systems, they present few stability issues ( outside of formula to be extra viscous in consistency. rancidity or lipid oxidation ) and do not have microbiological contamination issues. n They are thicker than creams and can be total anhydrous systems or n Because of their high viscosity or thickness, problems in contain a very low amount of water. Most are heavy or greasy as manufacturing can arise especially in compounding and filling. they contain lanolin, petroleum and mineral oil as the main constituents. n Examples of products that are ointments in nature are : n Hair Pomades n Medicated Skin Products n Ethnic Hair Treatment Items

20 3/7/13

SUSPENSIONS SUSPENSIONS

n From a stability perspective, suspensions usually contain either an inorganic thickener or structurizing polymer which “lock” the n This product form is related to emulsions, are usually water-based particles in place. This counteracts instability such as Van Der Waals formulations which contain larger, often visible products or hydrophobe/ lipophobe interactions suspended throughout. n Production of suspensions is generally easier than producing n They can range in viscosity and this type of product form offer a emulsions as separate mixing kettles are rarely required. unique visual effect to the consumer not observed in other n Examples of suspensions are : cosmetic products. n (encapsulated emollients) n By means of suspensions one can deliver non compatible n Sunscreen lotions with titanium dioxide or zinc oxide ingredients. n Calamine lotion n Antiperspirant sticks

GELS GELS

n This product form can be defined as clear, shear thinning n In the manufacturing process large scale production is complicated by formulations. They are composed usually of water or alcoholic their high viscosity. AIR entrapment is common place during this solutions gelled or thickened with specific gelling agents such as manufacturing mode and careful mixing is required to avoid this from natural gums, acrylic polymer or cellulosic type polymers. happening. n Examples of gels include:

n There is a special type of gel system which can be made called a micro n Shower Gels emulsion or “RINGING” gel that vibrates or rings when you tap the n Shaving Gels container. n Toothpastes n Ethnic “Shine” Hair Products (Microemulsion)

21 3/7/13

STICKS STICKS

n This is a product type which can be used to deliver insoluble n Sticks can be made as a sodium stearate type or as a pure materials such as fragrances, pigments, emollients and stick from high melting point ingredients such as waxes, specific active ingredients. hydrogenated oils and esters. n They are usually opaque but can, in some cases, be n Stick formulations have good stability profiles as their solid formulated as clear products. structure inhibits most destabilizing processes. n Examples of stick personal care products are:

n Deodorant sticks

n Antiperspirant sticks

n Hair styling sticks

n Lipsticks

POWDERS POWDERS

n Powders present the simplest form of a solid dosage form. Powders are a relatively stable product form and They consist of solid raw materials blended together in a during the manufacturing process involving fine mixture. specialized mixing equipment, it becomes critical to n Common ingredients that are utilized in the formulation of avoid contamination with water. powders include: n Examples of powder personal care products are:

n Talc n Baby powders

n Starch n Anti-fungal powders n Titanium dioxide n Body talc n Silicates

22 3/7/13

AEROSOLS AEROSOLS

n In compounding the active materials are mixed with the solvent and then this concentrate is filled into the can. The n In contrast to the product forms discussed earlier, aerosols propellant is added and the can is sealed. depend more on the packaging for their existence than n Stability issues are primarily of can corrosion and can be the ingredients. prevented by adding corrosion inhibitors to the formula n Aerosols are composed of a concentrate solution that is with high water contents. filled into a metal can after being pressure-filled with a n Examples of aerosol personal care products are : propellant that is hydrocarbon or freon based. n Shaving creams

n Hair sprays n Aerosol antiperspirants & deodorants

n Feminine deodorant products

COSMETIC R&D LABORATORY q Pilot scale-up and production of formula with appropriate n The development of aesthetic and chemically stable stability testing. personal care formulations has its origin in the research q Intermediate sized experimental batch and appropriate and development department. stability testing. n The development of such formulations and the ultimate q Selection of proper processing equipment for full manufacturing and production can be visualized in the production-sized run. product development “ CASCADE” of steps as follows : q Process evaluation and validation. n Formulation “ BRAINSTORMING” n Prototype development and panel testing. q What are the needs in the way of equipment for the n Formula optimization and selection for desirable research and development laboratory in order to help aesthetic/ marketing parameters. begin the “product development cascade” of events? n Stability testing of lab prepared samples.

23 3/7/13

BASIC LABORATORY EQUIPMENT BASIC LABORATORY EQUIPMENT

n Mixer-stirrers either electric or air driven equipped with both propeller and sweep ( simulated) shafts to simulate production n Viscometer capable of processing equipment. determining viscosity of very fluid liquid systems to thick viscous creams and ointments.

• pH meter for assessing specific acidity or alkalinity of a formulation. OPTIONAL LABORATORY EQUIPMENT n Centrifuge for additional analytical and stability testing. n Cone penetrometer for relative “ HARDNESS” of creams, gels, ointments etc. n Analytical instrumentation in conjunction with quality assurance lab equipment for advanced needs. • Heating device ( hot plate or mantle) for preparation of formulations requiring thermal energy. n IR spectro photometer n HPLC n UV-visible Spectro photo meter

n Specific claim substantiation equipment ( EX- • Refrigerator and/or oven for minimum stability testing of Instron) formulations. n Lab homogenizer

24 3/7/13

STABILITY PARAMETERS AND TESTING STABILITY PARAMETERS AND TESTING

n Typical stress conditions used by formulators in the hope that product performance and appearance are not n Formulations in R&D routinely examine product stability using various procedures. adversely affected during the projected product shelf life include: n It is rarely possible to predict long term stability of any product, even after repeated examinations of the formula n Heating during and after exposure to artificially created stress n Freezing conditions. n Centrifugation n Within the cosmetic industry, shelf life projections are based on the formulators assessments of stability data in contrast to much more rigorous analytical testing that is found in the pharmaceutical industry.

n Cosmetic products may exhibit instability due to chemical EMULSION INSTABILITY TYPES changes of the individual chemical components or the n CREAMING presence of undesirable micro-organisms. n Separation into two or more layers having different phase concentrations and different particle size distributions.

n If one examines the various product forms discussed n Encountered in primarily fluid ( low viscosity) emulsions and earlier in this presentation, creams and lotions that are usually can be minimized by reducing droplet size. Will not emulsions by definition possess the greatest potential for occur if both phases have the same density. stability problems during the shelf- life of the product.

n EMULSION BREAKDOWN n Cosmetic formulations, especially emulsions dosage forms, n Usually preceded by a sequence of physical processes, are thermodynamically unstable systems. They obey the flocculation and coalescence, and can be caused by: basic laws of physical chemistry and tend to revert to states of lowest free energy. (I.e.- oil and water phases).

25 3/7/13

n INVERSION:

• Electrolytes

• Micro-organisms n Defined as the change from one type of emulsion • pH form to another with the “FLIP” of the continuous • Temperature extremes phase. • Mechanical stresses

n Rare, but can occur in certain types, of o/w systems. n Must monitor stability samples rigorously to Example Borax / Beeswax upon loss of water) determine extent of above physical processes

PREDICTIVE COSMETIC STABILITY TEMPERATURE TESTING OF EMULSIONS n Rule of thumb assumes three months storage at a temperature between 37 degree C and 45 degree n Cosmetic stability testing, in general has to do with the primary concerns of physical appearance and the C products use characteristics. n with no evidence of separation should guarantee stability of the formula at room temperature n Review of main parameters for emulsion instability: ( 25-30 degree Celsius) for one year.

26 3/7/13

n RHEOLOGY

TEMPERATURE n Formulators utilize the examination of rheological change as a predictive tool to assess emulsion n Above rule is based on principles of the arrhenius stability. equation which may not be valid for emulsions.

n This type of stability testing includes the use of n Based on the above it is an accurate point to state that stability testing of emulsions should not be viscometers and/or cone or needle penetrometers. based solely on high temperature testing.

PARTICLE SIZE

n STABILTY OF ACTIVES IN COSMETICS

n Testing of drug ( active) constituents in emulsions • Particle size measurement of the disperse phase in an using the Arrhenius equation requires storage at two emulsion requires careful interpretation. temperatures at which chemical decomposition may – A continuous increase in particle size should result in occur. The wider the separation between the emulsion instability unless the preparation is very temperatures the more reliable is the analysis. viscous. n The tendency of emulsions to separate at elevated temperatures may have effects on drug solubility and can alter reaction rates.

27 3/7/13

SUMMARY OF ACCEPTED GUIDELINES FOR OTHER TESTING ACCELERATED STABILITY TESTING

CONDITION TYPE OF ASSESSMENT 25°c ± 2°c One year SHAKING One week at 30°c or 40°c. 30 °c ± 2°c One year ( Equivalent to R.T) 40 °c ± 2°c Six months CENTRIFUGATION One or two hours. Freeze/ thaw Cycle repeatedly between 4 °c and 40 °c or 45 °c . LIGHT TESTING Fluorescent One to two weeks ( or longer). Xenon One to two weeks. Ultraviolet One to two weeks. Daylight One year.

PILOT SCALEUP OF COSMETIC PILOT SCALEUP OF COSMETIC FORMULATIONS FORMULATIONS n It is not unusual for a formula which has been n Process Scale-up involves: successfully developed in the R&D lab to exhibit different characteristics when it is transferred to n The successful duplication of a formulation’s primary production. As the formula is transferred from a small, physical characteristics over a specific range of laboratory-scale apparatus to large-scale production increasing batch sizes. equipment, a difference in condition is experienced.

28 3/7/13

GOALS OF SCALE-UP n The successful duplication of a formulation’s primary physical characteristics over a variety of manufacturing equipment. n Batch Reproducibility n Upon successful scale-up you can trouble shoot:

n n Manufacturing issues Quick startup in manufacturing.

n Formulation issues n Increased profit to company.

n Equipment issues

n Raw material issues

REASONS FOR SCALE-UP n NEW REASONS:

TRADITIONAL REASONS: n Lower emulsifier levels

n Requires higher mechanical energy

n Right first time production batches n Better designed equipment with $ savings.

n Quicker to market for company Scale-up technique involves R&D pilot batches which require time and patience on the part of the formulator.

n Less downtime

29 3/7/13

WHAT IS THE RATIONALE FOR PILOT EQUIPMENT? n Useful for stability test data analysis in tandem with that n For preparation of scaled-up versions of specific R&D which is obtained from laboratory batches formulations intermediate in size between laboratory ( 1-2 kg) and production ( 1000-2000 gallon) batches. n Additionally, equipment can be utilized for small-sized production batches which could not be manufactured n Applicable for the following product types: utilizing normal processing kettles. n Emulsions including creams and lotions

n Suspensoid systems including gels and sticks.

n Non-Suspensoid systems and miscellaneous product types.

MANUFACTURING IN THE PLANT n In summary the overall benefits of formulation scale-up in the cosmetic industry are as follows: ENVIRONMENT

n Provides a smoother transition of manufacturing procedures from the laboratory to the plant environment. n In our previous discussion of scale-up we examined the overall reasons and benefits for pilot batches and n One can obtain fewer failures on first-time procedures as they relate to cosmetic formulations. production batches.

n From an efficiency perspective, one can realize a quick production start-up with less scrap and n It is generally believed that scale-up is am engineering rework. function. In essence, it is a dual function between the formulator and the process team in the plant.

30 3/7/13

n Without going into detailed engineering equations n As the given formulation is guided through the scale-up regarding mixing criteria the key points to consider in the stages for plant production there are number of key areas plant setting for this procedure are that become critical to the overall process: n Impeller dimensions and types n Impeller speed n Mixing n Impeller diameter to tank diameter referred to as the O/T ratio. n Heat transfer n Turnover rate ( number of batch turnovers per unit time) n Mass transfer n Flow profile based on the impeller and vessel configuration and batch loading.

PROCESS ROBUSTNESS n Heat transfer variables primarily involve:

n Heat transfer medium n Within the pharmaceutical industry there is a term that is n Heating and cooling rates used which can be transferred to personal care manufacturing. That term is called PROCESS ROBUSTINESS. n Maximum and minimum temperatures

n ROBUSTINESS is defined as “ the ability of a manufacturing n Lastly, mass transfer primarily is concerned with phase process to tolerate the expected variation of raw materials, transfer rates. operating conditions, process equipment, environmental conditions and human factors.” n It is important to understand that not all products react adversely with bench-to-production variations. There are n In order to develop a robust manufacturing process there many products robust enough to withstand all but the are six steps which need to be followed: most extreme variation.

n Team formation n Define the process n Prioritize experiments

31 3/7/13

RHEOLOGICAL CONSIDERATIONS AND n Analyze measurement capability n Identify functional relationships BATCH PROCESSING n Confirm critical quality attributes and critical process n Definition of basic concepts: parameters.

n n Creating a system that facilitates increased process Rheology- Study of the flow of matter. understanding and leads to process robustness benefits n Viscosity- The measure of the matter’s the manufacturer through quality improvements and resistance to the flow. cost reduction. n Rate of shear- The measure of movement of matter depending on force applied. n Information about the process setting and key n Viscosity= Shear stress/ rate of shear relationships are communicated to manufacturing. Upon transfer, manufacturing begins to verify R&D’s information on process robustness through process monitoring and data analysis. Both general and process specific improvement activities help manufacturing attain and maintain its goals.

PROCESSING PARAMETERS AND n Emulsions are systems where the viscosity varies with the rate of shear. This is in contrast with typical PROBLEMS Newtonian systems where viscosity is independent of n FACTORS INFLUENCING VISCOSITY the rate of shear.

1. Temperature of various processing steps n Emulsions can also exhibit:

n Individual phases before emulsification

n Thixotropic properties- viscosity decreases with shear time. n Phases upon combination

n Cooling water temperature n Rheopectic properties- viscosity is a function of duration of the applied stress; viscosity increases n Blend pumped out of process vessel. with shear time ( rare in emulsion systems).

n Blend at filling point.

n 32 3/7/13

2. Mechanical work MIXING EQUIPMENT AND IMPLICATIONS

n Shear of mixing n n Homogenization or milling Extremely critical parameter for emulsion systems. n Transfer work ( pipes, values, nozzles, etc) 4. Time factors n In a highly thixotropic emulsion with a high yield value, n Heating period avoid a small propeller as only a small portion of fluid n Cooling period near the propeller would move. A larger diameter n Mixing period propeller ( paddle type) would ensure for better mixing.

n All factors do not operate independent of each other. Ex-reducing mixing speed to minimize shear thinning results in decreased cooling efficiency. n Flow to fluid shear ratio is the term used in engineering to judge mixing requirements.

EFFECTS OF VISCOSITY ON PROCESSING CONDITIONS

n In an emulsification process, a high shear level ( high speed mixer) is needed, while in heat transfer steps, n Product viscosity can directly influence the mixing and such as heating and cooling, high flow ( low speed cooling rate. mixer) is desirable. n In a high viscosity emulsion, the heat transfer efficiency is lower and, therefore, so is the rate of cooling. n Similarly, a high viscosity product or a shear thickening n A proper combination of the above two mixing procedures will yield the desired processing result. product can cause both pumping and filling problems under production conditions.

33 3/7/13

n AIR ENTRAPMENT is common in high viscosity products. This is dependent on : n Solutions for de-aeration include:

n n Amount of air “trapped” during processing and Gentle heating. filling. n Impeller size and / or speed adjustment.

n Amount of air escaping after entrapment. n Varying pumping procedure.

n A shear thinning system tends to aerate much easier than either Newtonian or shear thickening n Use of vacuum deaerator such as a versator. formulations

PUMPING VARIABLES DURING PROCESSING 1. SHARE POSITIVE DISPLACEMENT TYPE Diaphragm--- Good for liquid, low shear n Critical equipment for proper processing and filling of cosmetic type formulations. Gear--- Impart high shear Moyno--- Impart low to medium n Two basic types of pumps used for cosmetic processing: 2. Centrifugal type

Works on principle of conversion of contrifugal force into pressure. This type of pump will not function at very high pressure or viscosities.

34 3/7/13

COOLING CONDITIONS DURING PROCESSING PROCESS VALIDATION CONCEPTS

n DEFINITION- establishing documented evidence n This is critical in emulsions, as rate of cooling affects the which provides a high degree of assurance that a final viscosity. Some products require slow cooling, specific process will consistently produce a product “ ” while others require FORCED COOLING through use meeting pre-determined specifications and quality of a water jacket. attributes. n TWO BROAD TYPES OF VALIDATION n Temperature and seasonal factors can impact cooling Prospective--- That done for a new product or revised time in non-air-conditioned environments. Use of a manufacturing conditions. chiller may be essential.

Retrospective--- That done for a product already in n Similar in format to a total quality assurance standard operating procedure ( SOP) with special emphasis distribution. placed on particular areas such as :

n Fundamental concept is documentation of protocols n Gauge calibration and/or procedures so as to identify the “KEY” areas n Preventive maintenance which require special attention. n Statistical analysis

n Emphasis of process validation is on prevention which is identical with the concept of quality management.

35 3/7/13

PROCESS EQUIPMENT OVERVIEW

36