Chapter 4

Dosage Form Design: Pharmaceutical and Formulation Considerations

Reasons For The Need of Dosage Forms

1. To provide for the safe and convenient delivery of dosage 2. For the protection of a drug substance from the destructive influence of atmospheric oxygen or Examples: coated tablets, sealed ampules 3. For the protection of a drug substance from the destructive influence of gastric acid after oral administration. Example: enteric coated tablets 4. To provide liquid preparations of substances that are either insoluble or unstable in the desired vehicle. Example: suspension accurate

moisture.

Reasons For The Need of Dosage Forms

5. To conceal the bitter taste, salty obnoxious or odor of a drug substance.

Examples: Capsules, coated tablets, flavored syrups 6. To provide liquid dosage forms of substances soluble in desired vehicle. Example: solution 7. To provide extended drug action through controlled release mechanisms Examples: controlled release tablets, capsules, suspensions

Reasons For The Need Of Dosage Forms

8. To provide optional drug action from topical sites administration nasal orifices

Examples: ointments, creams, ophthalmic, ear and preparations 9. To provide for insertion of a drug into one of the bodys Examples: rectal and vaginal suppositories 10. To provide for the placement of drugs within body tissues.

11. To provide for the optimal drug action through

Examples: inhalants and inhalations 12.

inhalation therapy.

addition, many dosage forms permit ease of drug identification through distinctiveness of color, shape, or identifying markings

In

*** There is a variety of dosage forms that a medical agent may be placed for the convenient and effective treatment of disease.
Example: Prednisolone a synthetic adrenocortical steroid used for antiinflammatory activity on various parts of the body. The Various Forms of Prednisolone: tablet, sterile suspension for injection, solution for injection, ophthalmic preparation, sterile powder for reconstitution

THE NEED FOR DOSAGE FORMS

The majority of drug substances are administered in manufacturing amounts, much too small to be weighed on anything but a sensitive analytical balance. Example: How can a layman accurately obtain 325 mg or 5 gr of aspirin found in common aspirin tablets from bulk supply of aspirin? Examples Of Drugs with Low Usual doses
Ferrous sulfate Cimetidine Amoxicillin Propoxyphene HCl Phenobarbital Diphenhydramine HCl Morphine sulfate Cochicine Nitroglycerin Digoxin Ethinyl Estradiol 300 mg 250 mg 65 mg 30 mg 25 mg 10 mg 0.5 mg 0.4 mg 0.25 mg 0.05 mg 300 mg Antiulcer Antibacterial Analgesic Sedative Antihistamine Narcotic Analgesic Gout suppressant Antianginal Cardiotonic Estrogen Hematinic

Some Drugs With Relatively Low Usual Doses

Drug
Betaxolol Clotrimazole Methylphenidate HCl

Usual Dose (mg)

10.00 10.00 10.00

Category
Antianginal Antifungal CNS stimulant

Medroxyprogesterone acetate 10.00

Mesoridazine besylate Nifedifine Omeprazole 10.00 10.00 10.00

Progestin
Antipsychotic Coronary vasodilator Antiulcerative

Quinapril HCl
Chlorazepate dipotassium Buspirone HCl Enalapril maleate

10.00
7.50 5.00 5.00

Antihypertensive
Tranquilizers Antianxiety Antihypertensive

Hydrocodone
Albuterol sulfate Chlorpheniramine maleate Felodipine

5.00
4.00 4.00 2.50

Narcotic analgesic
Bronchodilator Antihistaminic Vasodilator

Some Drugs With Relatively Low Usual Doses

Drug
Glyburide 2.50

Usual Dose (mg)

Category
Antidiabetic Antihypertensive Narcotic analgesic

Doxazosin Mesylate 2.00 Levorphanol tartrate 2.00

Prazosin HCl
Risperidone Estropipate Bumetanide

2.00
2.00 1.25 1.00

Antihypertensive
Antipsychotic Estrogen Diuretic

Clonazepam
Ergoloid mesylates 1.00 Alprazolam Levothyroxine

1.00

Anticonvulsant
Cognitive adjuvant

0.50 0.10

Antianxiety Thyroid

Misoprostol

0.10

Antiulcerative

General Considerations In Dosage Form Design

Drug substances are seldom administered in their natural or pure state, but rather as part of a formulation in combination with one or more nonmedicinal agents that serve varied and specialized pharmaceutical functions Through selective use of these non-medicinal agents, referred to as pharmaceutical aids, pharmaceutical ingredients, adjuncts or necessities, pharmaceutical preparations of various type result.

It is the pharmaceutical adjuncts that serves to solubilized, suspend, thicken, dilute, emulsify, stabilize, preserve, color, flavor and fashion the many and varied medicinal agents into effective and appealing pharmaceutical preparations.
The term Pharmaceutics which is the study that concerns itself with the physical, chemical and biological factors which influence the formulation, manufacture, stability and effectiveness of pharmaceutical dosage forms.

GENERAL CONSIDERATIONS IN DOSAGE FORM DESIGN

1. Drug Consideration In Dosage Form Design 1.1 Characteristics of Drug Substances

1.2 Drug Stability

1.3 Determining Drug Formulation Stability 1.4 Prevention Against Microbial Contamination 1.5 Appearance and Palatability

2. Therapeutic Considerations In Dosage Form Design

2.1 Nature of the disease or illness 2.2 Age of the Patient 3. Biopharmaceutics Considerations

3.1 Biopharmaceutics
3.2 Concept of Bioavailability

1.1 Characteristics of Drug Substances

A. Liquid medicinal agents Problems: 1. Volatile substances 2. Liquid intended for oral administration cannot formulated into a tablet form, the most popular of oral medication, without modification. The medications are of 2 approaches

- liquid substance is sealed in a soft gelatin capsules

- liquid substance is develop into salt form to convert into solid Example: Arecoline and Scopolamine are liquids and they are converted into Hydrobromide form as solid

B. Solids medicinal agents

Most preferred by the researchers due to the following Advantages: 1. Stability 2. Ease of handling 3. Could be made into tablet and capsules - the most common dosage forms

1.2 DRUG STABILITY

a. Centered around the chemical stability of the medical agents b. Its compatibility with other formulative ingredients

Unstability may be noticed by the following conditions: 1. Precipitation of a chemical agent from the solution 2. Evolution of gas resulting an odor release or container breakage

3. Alteration in the color of solid or liquid dosage form

4. Change in liquid characteristics of a liquid preparation

5. Rancid odor of an ointment

The Most Encountered Destructive Process In Drug Formulation

1. Hydrolysis is the process in which drug molecule
interact with water molecules to breakdown products of different chemical constitution. Example: Aspirin yield

Aspirin

Water

Salicylic acid

+ Acetic acid

*** So stabilize such preparation

1. Apply waterproof protective coating over the tablets 2. Enclose tablets in tightly close container

In case of liquid formulation 1. The use of anhydrous vegetable oils as vehicle 2. Substituting liquids such as glycerin, propylene glycol and alcohol for water

NOTE: For certain unstable antibiotic drugs, when an aqueous preparation is desired the form for reconstitution is supplied then adding a specified volume of purified water just before dispensing.

2. Oxidation is a destructive process occurring in

pharmaceutical. Chemically, it involved the change in the number of electrons from an atom or molecule.

Oxidation occurs when the drug is:

1. Not in the dry state 2. Maintained in the presence of oxygen and light 3. Incompatibilities with chemical agents in a formula

Remedied by the use of:

1.

which act by providing electrons and easily available hydrogen atoms that acceptable more readily by the free radicals (atoms containing one or more unpaired electrons as molecular oxygen O-O or free hydroxyl group (OH) Examples of Antioxidants: Na2SO3 , NaHSO3, H3PO2 and Ascorbic

Antioxidants

In oligeanous preparation - alpha tocopherol, BHA (butylhydroxyanisole), BHT (butyl hydroxytoluene) and ascorbyl palmitate.

2. In common practice, vials and ampules of easily oxidizable preparations for parenteral use are packed in sealed container with inert gas nitrogen replacing oxygen during process.
3. 4. Protection from light by using light resistant glass container Storage in a cool place for drugs affected by increase in temperature

EXAMPLES: Epinephrine preparations - Adrenergic do not use the if it is brown or contains precipitate Nitroglycerin Tablets - Antianginal - to prevent loss of potency, keep these tablets in the original container Paraldehyde - Hypnotic - subject oxidation to form acetic acid to

1.3 Determining Drug Formulation Stability

1. Physical Properties changes like physical
appearance, color, odor, taste, or texture of the formulation

2. By Chemical changes through analysis

Reaction Kinetics study of the rate of chemical change and the way it is influenced by factors like drug concentration, solvent used, temperature and pressure and presence of other chemical agents. Accelerated Stability Testing the use of exaggerated conditions of temperature, humidity, light and others, to test the ability of the drug formulation

Purposes of these Tests

1. Drug product stability
2. Shelf - life

3. Expiration dating

5 Types Of Stability
1. Physical Stability means that the original physical properties like appearance, palatability, viscosity, uniformity of color maintained until expiry date. 2. Chemical Stability means that the active ingredient retains its chemical integrity and labeled potency are retained over extended period of time.

3. Microbial Stability means that the activity or resistance to microbial growth should still according to specified requirements. Preservatives must be added to prevent the growth of microorganism. 4. Therapeutic Stability means that the therapeutic effect maintained until expiry date.

5.

Toxicological Stability means when no significant increase in toxicity has occurred.

Preformulation Studies
1. Physical Description
@ crystalline or amorphous constitution @ identification and evaluation of its chemical, physical and biologic properties @ Chemical properties - structure, form and reactivity @ Physical properties - particle size, crystalline structure, melting point and solubility @ Biologic properties - ability to get to a site of action and elicit biologic response

2. Microscopic Examination
@ indication of particle size and size range of the raw material along with the crystal structure @ the solid drug powders must flow freely and not become entangled @ spherical and oval powders flow more easily than needle-shaped powders and make processing easier

@ photomicrographs of the drug can provide information in case of problems in formulation processing attributable to changes in particles

3. The Phase Rule

@ to provide a visual picture of the existence and extent of the presence of solid and liquid phases in binary, ternary, and other mixtures. @ phase diagrams are normally twocomponent

4. Particle Size
@ physical and chemical properties of drug substances, including dissolution rate, bioavailability, content uniformity, taste, texture, color, and stability are affected by the particle size distribution. @ establish as early as possible how the particle size of the drug may affect formulation and efficacy @ the effect of particle size on absorption (oral absorption of griseofulvin, nitrofurantoin, spironolactone, and procaine penicillin

5. Polymorphism
@ important factor on formulation is the crystal or amorphous from of the drug substance. @ the amorphous form of a compound is always more soluble than a corresponding crystal form @ the most widely used methods are hot stage microscopy, thermal analysis,infrared spectroscopy, and x-ray diffraction.

6. Melting Point Depression

@ a characteristic of a pure substance is a defined melting point or melting range.

@ if not pure, the substance will a change in melting point

exhibit

7. Solubility
@ a drug must possess some aqueous solubility for therapeutic efficacy @ for a drug to enter the systemic circulation and exert a therapeutic effect, it must first be in solution. @ chemical modification of the drug into salt or ester forms is frequently used to increase solubility

@ a drug solubility is usually determine by the equilibrium solubility method, by which an excess of the drug is placed in a solvent and shaken at a constant temperature over long period until equilibrium is obtained
@ chemical analysis of the drug content in solution is performed to determine degree of solubility.

8. Solubility and Particle Size

@ Solubility is normally considered a physicochemical constant, small increases in solubility can be accomplished by particle size reduction.

9. Solubility and pH
@ another technique, if the drug is formulated into a liquid product, pH adjustment of the solvent to enhance solubility.

@ weak acid or basic drugs may require extremes in pH that are outside accepted physiologic limits or that may cause stability problems with formulation ingredients. @ adjustment of pH has little effect on the solubility of the substances other than electrolytes.
@ it is desirable to use cosolvents or other techniques such as, complexation, micronization, or solid dispersion to improve aqueous solubility

10. Dissolution
@ dissolution rate, or time it takes for the drug to dissolve in the fluids at the absorption site, is the rate-limiting step in absorption. @ when the dissolution rate is the rate- limiting step, anything that affects it will also affect absorption.

@ the dissolution rate of drugs may be increased by decreasing the drugs particle size.
@ it may also be increased by increasing its solubility in diffusion layer

@ the most effective means of obtaining higher dissolution rates is to use a highly water soluble salt of the parent substance @ dissolution rates of chemical compounds are determined by 2 methods:
1. Constant-surface method - which provides the intrinsic dissolution rate of the agent 2. Particulate dissolution - in which a suspension of the agent is added to a fixed amount of solvent without exact control of surface area.

Constant-surface method - uses a

compressed disc of known area and surface electrical charges as dissolution variables. The dissolution rate obtained by this method, the intrinsic dissolution rate, is characteristics of each solid compound and a given solvent in the fixed experimental conditions. The value is expressed in milligrams dissolved per minute per centimeters squared.

Particulate dissolution
@ a weighed amount of powdered sample is added to the dissolution medium ian a constant agitation system. This method is used to study the influence of particle size, surface area, and excipients upon the active agent

Ficks Law
@ describe the relationship of diffusion and dissolution of the active drug in the dosage form and when administered in the body.

11. Membrane Permeability

@ to produce a biologic response, the drug molecule must first cross a biologic membrane. The biologic membrane acts as a lipid barrier to most drugs and permits the absorption of lipid-soluble substances by passive diffusion, while lipid insoluble substances can diffuse across the barrier only with considerable difficulty if at all. @ Everted intestinal sac may be used to evaluate absorption characteristics of drug substances. A piece of intestine is removed from an intact animal, everted, filled with a solution of the drugs substance, and the degree and rate of passage of the drug through membrane sac is determined.. This method allows evaluation of both passive and active transport.

12. Partition Coefficient

@ is the selection of appropriate extraction solvents, drug stability, use of salting-out additives, and environmental concerns. @ the octanol water partition coefficient is commonly used in formulation development (conc. of drug in octanol) @ P= ( conc. Of drug in water)

P depends on the drug concentration only if the drug molecules have tendency to associate in solution
@ in an ionizable drug, the following equation is applicable (conc. Of drug in octanol) P= [1- ] (conc. Of drug in water) where equals the degree of ionization

13. pKa/Dissolution Constant

@ important because the extent of ionization has an important effect on the formulation and pharmacokinetic parameters of the drug.

@ the extent dissociation or ionization in many cases is highly dependent on the pH of the medium containing the drug
@ in formulation, often the vehicle is adjusted to a certain pH to obtain a certain level of ionization of the drug for solubility and stability @ dissociation constant, or pKa, is usually determined by potentiometric titration.

14. Rate of reactions

@ the reaction rate is description of the drug concentration with respect to time. Most commonly, zero-order and first-order reactions are encountered in pharmacy

@ if the loss of drug is dependent of the concentration of the reactants and constant with respect to time (I.e 1 mg/mL/hour) the rate is called zero order.
@ if the loss of drug is direct proportional to the concentration remaining with respect to time, it is called a firstorder reaction and has the units of reciprocal time that is, time-1.

15. Q10 Method of Shelf Life Estimation

@ estimate shelf life for a product that has been stored or is going be stored under a different set of conditions.
Some USP Drugs and Preparations Especially Subject to Chemical or Physical Deterioration Preparation Category Monographs or Label Warning

to

Epinephrine bitartrate ophthalmic solution inhalation solution adrenergic injection Epinephrine nasal solution Epinephrine ophthalmic solution

Do not use inhalation, injection, nasal, or ophthalmic solution if it Epinephrine is brown or contains a precipitate Epinephrine

Isoproterenol sulfate
Inhalation, solution

Do not use inhalation or injec. (bronchodilator)if it is pink to brown/ppt.

adrenergic

Isoproterenol inhalation solution Nitroglycerin tablets Antianginal To prevent loss of potency, keep in original container or supplemental container specifically labeled suitable fot nitroglycerin tablets Subject to oxidation to form acetic acid

Paraldehyde

Hypnotic

Signs Of degradation Of Specific Dosage Forms

1. Tablets
2. Capsules

appearance, friability, harness, color, odor, odor, moisture content, and dissolution
strength, moisture, color, appearance, shape, brittleness, and dissolution

3. Oral solutions appearance, strength, pH, color, odor, suspensions redispersibility (suspension), and clarity (solutions) 4. Oral Powders 5. Metered-dose inhalation aerosols 6. Topical non metered aerosols appearance, strength, color, odor, moisture strength, delivered dose per actuation, number of metered doses, color of propellant, pressure, valve, corrosion, spray pattern, absence of pathogenic microorganism appearance, odor, pressure, weight loss, net weight dispensed, delivery rate, and spray pattern

7. Topical Creams ointments, lotions, solutions, and gels: appearance, color, homogeneity, odor, pH, resuspendibility (lotions), consistency, particle size, distribution, strength, weight loss

Signs Of Degradation Of Specific Dosage Forms

8. Ophthalmic Preparations appearance, color, consistency, pH, clarity (solutions), particle size, resuspendibility (suspensions, creams, ointments), strength, and sterility 9. Parenterals strength, appearance, color, clarity, particulate matter, pH, volume and extractables (when plastic containers are used), sterility, pyrogenicity, and closure integrity 10. Suppositories dissolution 11. Emulsion strength 12. Transdermal seal strength of the drug reservoir, decomposition products, membrane drug strength, and drug release strength, softening range, appearance, and appearance, color, odor, pH, viscosity, and

integrity, rate

MODE OF ACTION FOR PRESERVATIVES

Preservatives interfere with microbial growth, multiplication, and metabolism through one or more of the following mechanisms
1. Modification of cell membrane and leakage of cell constituents (partial lysis) 2. Lysis and cytoplasmic leakage 3. Irreversible coagulation of cytoplasmic constituents precipitation) (protein

4. Inhibition of cellular metabolism as through interference with enzymes systems or inhibition of cell synthesis 5. Oxidation of cellular constituents

6. Hydrolysis

Probable Modes Of Action Of Some Preservatives

1. Benzoic acid, boric acid, p-hydroxybenzoates: Denaturation of proteins 2. Phenols, chlorinated phenolic cmpds: lytic, denaturation action on cytoplasmic membranes and for chlorinated preservatives, also by oxidation of enzymes 3. Alcohols: lytic and denaturation action on membranes

Quaternary compounds: Lytic action onmembranes

4. Mercurials: Denaturation of enzymes by combining with thiol (-SH) groups

1.4 PRESERVATION AGAINST MICROBIAL CONTAMINATION

Considerations to be taken in selecting preservations
1. The preservatives is effective in preventing the growth of the type of organism which is the most contaminants of the formulation. 2. Soluble in water to achieve adequate concentrations in the aqueous phase of a 2 or more phase system.

3. The proportion of preservative remaining undissociated at the pH of the preparation makes it capable of penetrating the microorganism and destroying it.
4. The required concentration of the preservative does not affect the safety comfort of the patient upon administration. 5. Preservative should be stable. 6. Preservatives should be compatible with all other ingredients of the formulation. 7. Should not adversely affect the preparations container or closure. or

Examples:
Benzoic acid (0.1 to 0.2%),

Sodium benzoate (0.1 to 0.2%),

Alcohol
Phenol Cresol Chlorobutanol

(15 to 20%),
(0.1 to 0.5%), (0.1 to 0.5%), (0.5%),

Benzalkonium Chloride (0.002 to 0.01%), combination of methylparaben and propylparaben (0.1 to 0.2%)

1.5 APPEARANCE AND PALATABILITY

Most drug substance in use today are unpalatable and unattractive in their natural state, modern pharmaceutical preparation present them to the patient as colorful, flavorful formulations attractive to the sight, smell and taste.

Proper combination of color, fragrance and taste of a preparation is a challenge requiring, a specialized skill that must be applied with great care.
Flavoring of pharmaceuticals applies primarily to the liquid dosage forms intended for oral administration Today, the taste of foods and drugs are generally classifies into 4 main groups: sweet, salty, bitter and sour with such additional taste as metallic and alkaline sometimes giving reference. Sweet and Salty are perceived by the taste buds located near the tip of the tongue, sour at the sides of the tongue and bitter at the back

Flavoring Agents
To mask effectively the unwanted or disagreeable taste of drugs
***

In general, low molecular weight are salty, like NaCl, KCl, NH4Cl, NaBr and higher molecular salts are bitter except some lead salts. Examples: Anise oil, Cinnamon, Peppermint, and Orange With organic compounds, an increase in the number of OH group seems to increase the sweetness of the compound. Sucrose which has 8 OH groups is sweeter than glycerin which has 3 OH groups.

Certain flavoring materials have been found through experience

1. Cocoa - flavored vehicles effective for masking bitter taste 2. Fruits or Citrus flavors for masking sour or acid drugs tasting

3. Orange, Cinnamon, Strawberry for improving taste of salty drugs

Coloring Agents Uses: 1. For aesthetic value

2. Sensory adjuncts to the flavors employed

Different Types of Flavors

1. Natural Flavor:
Essential oil, oleoresin, essence or extractive, protein hydrolysate, distillate, or nay product of roasting, heating or enzymolysis, which contains the flavoring constituents derived from a spice, fruit, or fruit juice, vegetables, edible yeast, herb , bark, bud, root, leaf or similar plant material, meat, seafood, poultry, eggs, dairy products or fermentation products thereof whose significant function in food is flavoring rather than nutritional

2. 3.

Artificial Flavor:
derived above. from a

Any substance used to impart flavor that is not spice, fruit, vegetables or anything mentioned

Spice:

Any aromatic vegetable substance in whole, broken, or ground from, except substances traditionally regarded as foods, such as onions, garlic, celery; whose significant function in food is seasoning rather than nutritional; that is true of any volatile oil or other flavoring principle has been removed.

Commercial Flavor Designation

Natural ABCD flavor: All components derived from ABCD

ABCD flavor, natural and artificial: At least one component derived from ABCD. NO definition of natural to artificial ratio ABCD flavor,WONF: All components natural. At least one component derived from ABCD Natural flavor, ABCD Type: All components are natural. No components derived from ABCD ABCD flavor, artificial: All components are artificial Conceptual flavors: May contain artificial flavors. No reference point. May only have to declare in ingredient declaration

Water soluble flavors: Generally start at 0.2% for artificial and 1-2% for natural flavors. Oil-soluble flavors: Generally start at 0.1% in finished product for artificial flavors and 0.2% for natural flavors Powdered flavors: Generally start at 0.1% in finished product for artificial flavors and o.75% for natural flavors

Comparison Of Sweetness
Sucrose Source sugar cane; sugar beet Saccharin chemical synthesis; phthalic anhydride, petroleum product Aspartame chemical synthesis; methyl ester, dipeptide of phenylalanine and aspartic acid Relative Sweetness 1 Bitterness Aftertaste none none 300 180-200 none none

moderate strong moderate strong; sometimes metallic or bitter

Calories Acid Stability Heat Stability

4/g good good

0 excellent excellent fair poor

4/g

Sweetening Pharmaceuticals
Saccharin = metabolized and excreted by the kidneys virtually unchanged Cyclamate = metabolized or processed in digestive tract and its by product excreted by the kidneys Aspartame = breaks down in the body into three basic components: the amino acids phenylalanine and aspartic acid, and methanol @ because of its metabolism to phenylalanine, the use of aspartame by persons with phenylketonuria (PKU) is discourages, and diet foods and drinks must bear appropriate label warning. @ saccharin and cyclamate were generally recognized as safe or what is known as GRAS Acesulfame = is more stable than aspartame at elevated temperature; it is in candy, chewing gum, confectionery, and instant coffees and teas Stevia powder = Stevia rebaudiana bertoni. It is natural, nontoxic, safe, and about 30 times as sweet as cane sugar, or sucrose use are

Coloring Pharmaceuticals
Distinction between agent and coloring agent
Sulfur = yellow; Riboflavin = yellow;

Rupric sulfate = blue;

Ferrous sulfate = bluish green; Cyanocobalamin = red; Red mercuric iodide =vivid red

Sources Of Coloring Agents

Most pharmaceutical colorants are synthetic origin, few are naturally occurring principles obtained from mineral, plants and animal source

Example: red ferric oxide is mixed in small portions with ZnO powder to prepare calamine giving the latter a characteristic pink color intended to match the skin done upon application.
Chlorophyll in green plants impart its color to many products The synthetic coloring agent come mostly from coal tar (pix carbonis) black, viscid liquid which is a by product in the destructive distillation of coal.

Approved Color Additives Are Classified Into 3 Groups

1. FD & C dyes - legally used in food, and cosmetics drugs

2. D & C dyes - legally used in drugs and cosmetics 3. External D & C dyes - legally used only to color externally applied drugs and cosmetics

FACTORS TO BE CONSIDERED IN THE SELECTION OF COLORANT OR DYE 1. Certified dye 2. Gives aesthetic value 3. Physical and chemical properties 4. pH or pH stability of the preparation

CERTIFICATION
Synthetic dyes used internally should be certified

Characteristics of a dye before gaining certification

1. Must be safe

2. Must not interfere with the therapeutic efficacy of the product

3. Must not interfere with the assay procedure for the preparation

AESTHETIC VALUE
Liquid preparations - the amount is ranging from 0.0005 to 0.001% depending upon the colorant and intensity desired Solid or powdered, Compressed Tablets - generally larger proportion is required (0.1%) Ointments, suppositories, opthalmic and parenteral -no color additives

FACTORS TO BE CONSIDERED IN THE SELECTION OF COLORANT OR DYE

1. PHYSICAL AND CHEMICAL PROPERTIES
Solubility of the dye should be the first to be studied in the solvent or vehicle used. Dyes may be grouped into
a. Water soluble b. Oil soluble

2. pH
Dyes can change color with a change of pH. The color must be chemically stable in the environment of the other formulative ingredients for the shelf life

Examples of color formulation

1. Orange 2. Cherry 3. Strawberry 4. Grape Yellow #6, #5 and Red #40 Red #40 and Blue #1 Red # 40 and Red #3 Red #40 and Blue #1

5. Lemon
6. Chocolate

Yellow # 5
Red # 40, Yellow #5 and Blue #1

5 Categories of Evidence of Carcinogenic Activity For Color Additives

1. Clear evidence of carcinogenic activity

2. Some evidence
3. Equivocal evidence - indicating uncertainty 4. No evidence - indicating no observable effect 5. Inadequate study - for studies that cannot be evaluated because of major flaws

Changes are made in the list of certified colors in accordance with toxicology findings:
1. Withdrawal of certification 2. The transfer of a colorant from one certification category another 3. The addition of new colors to the list to

NOTE: Before gaining a certification, a color additives must be demonstrated to be SAFE

THERAPEUTIC CONSIDERATIONS IN DOSAGE FORM DESIGN 1. Nature of the disease or illness 2. Age of the patient Nature of the Illness a. Whether the illness is best treated systematically or locally b. Whether the illness is best treated with prompt, slow, short, or long acting pharmaceuticals c. If the illness can be safely treated through self medication where manufacturers prepare the dosage form in a compact dosage units like tablets or capsules or liquid form

Age of the patient

a. For infants - liquid pharmaceuticals are preferred rather than solid dosage forms to be administered drops Example: vitamin drops

by

b. Early childhood - difficulty in swallowing solid dosage form, syrup or chewable tablet are made. c. Adults - solid dosage forms