Dosage Form Design

Pharmaceutical and Formulation Considerations

➢ WHY DO WE NEED DOSAGE FORMS?

• To make the drug possible for human consumption
• To protect the drug from the destructive influences of the atmosphere
• To conceal offensive characteristics of the drug
• To provide control of drug release
• To provide multiple sites of administration depending on the situation

➢ PHARMACEUTICS VS BIOPHARMACEUTICS
• Pharmaceutics
▪ General area of study concerned with the formulation, manufacture, stability, and
effectiveness of pharmaceutical dosage forms
▪ Pharmaceutical Dosage Forms and Drug Delivery Systems
▪ Physical Pharmacy – focuses on stability of pharmaceutical dosage dorms
▪ Manufacturing Pharmacy – focus on manufacturing dosage forms on a large scale
• Biopharmaceutics
▪ The area of study embracing the relationship between the physical, chemical, and biologic
sciences as they apply to drugs, dosage forms, and drug action
▪ Focuses on what will happen to the drug once inside the body
▪ How excipients affects liberation and absorption
▪ Processes: LADME (Liberation, Absorption –for Biopharmaceutics) (Distribution, Metabolism,
Excretion – Kinetics)

➢ MASTER FORMULA
• Main recipe
• Drug standard catered to an institution

➢ Preparation – Compounded
➢ Product – Manufactured
• Example FENTANYL – analgesic (Strong Pain Killer)
 ▪ Lollipop – do not bite
▪ Transdermal patch
▪ Nasal spray
➢ PROBLEMS WITH DRUG ADMINISTRATION

➢ PREFORMULATION STUDIES
• Physical description – for identification purposes
▪ Chemical Properties
▪ Chemical Forms
▪ Reactivity
▪ Volatility – solid ester or salt form for a drug to become less volatile
- formulate into soft gel capsules
- combine with a semisolid material for incorporation into a hard gelatin capsule
• Microscopic examination – shape of a powder under a microscope since it will affect how you
compress capsules and compress tablets
*starting form of all dosage forms is a powder
*the more spherical, the easier
• Heat of Vaporization – laminar air flow hood
- anticancer drugs are very toxic, if vapor is inhaled, high chance of getting cancer
*cytotoxic – enters the cell
*scored tablet
• Melting Point Depression
• Particle Size – to know how fast it will dissolve, compression, etc
 ▪ Take shape into consideration for flow of granulation and for filling of solid oral dosage
forms
▪ Take size into consideration for fill and dissolution purposes, as well as interactions with the
environment

*Tablet Machine
• Polymorphism – multiple crystalline structures per drug
▪ Amorphous – structure is irregular
- melting point, absorption irregular
- dissolution is faster
▪ Crystalline – its chemical structure is tightly packed
- Melting point is always definite
- absorption is always constant
- dissolution will take longer
• Solubility
▪ Disintegration – Deaggregation – Dissolution
*drugs are important to dissolve to be absorbed in the intestinal tract
*steps of disintegration
Granules to powder – deaggregate
Powder to solution – dissolve
▪ Factors affecting solubility
o Particle size – lower particle size, higher surface area, higher rate of dissolution
o pH – dissolve better when different ph level
o Innate solubility characteristics
o Salt or ester form
o Temperature – higher temp, higher dissolution
o Pressure – gaseous dosage form
o Charge, ionization
*lipid soluble – able to pass through the blood brain barrier (drug is able to affect the CNS)
*Fick’s Law – test for diffusion
• Membrane Permeability- related to absorption to the intestines
- testing on mice, inject the drug, and see if the drug can penetrate to the cross-intestinal tract
• Partition Coefficient- related to absorption to the intestines
*PKA – drug will dissociate, ions will disperse
*cell Membrane – polar head, non-polar tail
o Gases can pass through
o Hydrophobic molecules
o Small polar molecules
o Large polar molecules cannot pass through the pores
o Charged molecules cannot pass through bcos it’s not charged on the outside
• Hydrates (water attached to it) and Solvates
*sucrose – a diluents
▪ Anhydrous – no water attached
▪ Monohydric
▪ Dihydric
▪ Hydroscopic- inherit water but does not dissolve
▪ Deliquescent – it will liquefy
▪ Efflorescent – releases water on its own
▪ Desiccant – absorbs moisture
• Organic Salt (substance that contains salt that has different pH on it)
*patients with hypertension should not be given sodium bcos they already have high amount
of sodium
*in order to form a salt, basic should be added to acid
*salts are very water soluble
 • Ester – RCOR
▪ Esterase – common enzyme in the body that destroys the ester group

➢ UNITS
• IU, USP units
• No relationship with other drugs;unique
• Standards of potency are done in the dried or anhydrous state

➢ PROTEIN DIGESTION
• Starts in the stomach

➢ DRUG PRODUCT STABILITY

• STABILITY PROBLEMS
▪ Chemical
▪ Physical
▪ Microbiological
▪ Therapeutic
▪ Toxicologic
*Aspirin is prone to hydrolysis
*Epinephrine – makes the heart stronger and beats faster
-prone to photo degradation and oxidation
- pink color – produce adrenochrome
- brown – melanin
- all catecholamine will degrade to melanin
*Amber bottles – resists lights passing through
(photons will not go inside the bottle)
*photons are catalyst, will speed up the chemical reaction
*if not in amber bottles, container must be covered with aluminum foil
*tightly-closed hermetic container
*sulfites are common antioxidants
*air displacement – nitrogen and carbon dioxide
*inert (no use) powder can be added as diluents

➢ STABILITY STUDIES
• Q10 method – environmental conditions are different
• Accelerated testing – subject the drug to higher temperature for stability
• Stress testing – submit the drug to very stressful conditions , weeks or days
• Expiration date and shelf-life

*RH – Relative Humidity

➢ USP GUIDELINES FOR STABILITY OF EXTEMPORANEOUSLY COMPOUNDED PREPARATIONS
PREPARATION RECOMMENDED SHELF-LIFE LABELING
Non-aqueous liquids and solids wherein the NMT 25% of the time remaining before
manufactured drug is the source of the preparation expiration or 6 months, whichever is earlier

Non-aqueous liquids and solids wherein a USP or NF 6months

substance is the source of the preparation

Water-containing formulations prepared from NMT 14days at cold-temperatures

ingredients in solid form

All others Intended duration of therapy or 30 days,

whichever is earlier
*antibiotics should be put in a refrigerator to slow the molecules therefore lower chemical reactions

➢ CHEMISTRY OF TASTE
• (Sodium, potassium, ammonium) chloride –salty
• (potassium and ammonium) bromide –salty and bitter
• Magnesium sulfate and potassium iodide -bitter
• Low molecular weight salts –salty
• High molecular weight salts –bitter
• Increasing hydroxyl groups –sweet
• Nitrogen containing –bitter

➢ ARTIFICIAL SWEETENERS
• Carriers
▪ Liquid carriers
o Oil-soluble
o Water-soluble
▪ Dry carriers
o Neotame
o Alitame
o Sucralose
o Saccharin
o Acesulfame K
o Aspartame
o Cyclamate

pp.412
*artificial(0.1-0.5) are more concentrated, more potent
*natural flavor (1-2 percent)

➢ Nutritive – has nutritional value

• Sugars –sucrose, dextrose, fructose, lactose
• Corn syrup
• High fructose corn syrup
• Sugar alcohols –polyols like hydrogenated glucose syrup (maltitol), mannitol, sorbitol, xylitol

➢ Non nutritive – no nutritional value

• High-intensity artificial sweeteners-acesulfameK, sucralose, aspartame, neotame, saccharin
• Natural intense sweeteners –glycyrrhizin, thaumatin, rebaudioside A
➢ COLORANTS
• Before, aniline from coal tar was used. Now, it’s aniline from petroleum
• FD&C or Food, Drug and Cosmetics
• D&C or Drug and Cosmetics
• External D&C – Cosmetics products that are applied topically, not included on lips and mouth
• Lakes – aluminum derivatives
- usually used in substances like hard gelatin capsules
- insoluble
• Oil-soluble dyes
• Water-soluble dyes
➢ TESTING OF COLORANTS
• 2 years with mice
• Results
• Safe
• “there is convincing evidence that establishes with reasonable certainty that no harm will
result from the intended use of the color additive”
RESULTS
Clear evidence of carcinogenicity
Some evidence
Equivocal evidence
No evidence
Inadequate evidence

➢ CARCINOGENIC COLORANTS
➢ STERILIZATION
• Sterile means that the substance completely lacks any living/ viable microbial life
• Maintained through the use of preservatives or other mechanical methods
*disinfectant – disease causing microorganisms are eliminated

➢ COMMON STERILIZATION METHODS

• Autoclaving – Moist heat sterilization, lower temp, shorter period of time]
*if there is moisture, the easier for heat to penetrate the membrane
• Dry Heat Sterilization – higher temp, longer period of time
• Filtration – high efficiency filter
- may filter out some of the drugs
- applicable to drugs that are heat labile and has small molecular weight
• Ionizing Sterilization – use UV lights
• Gas Sterilization – propelene oxide
- cause mutation

➢ REQUIREMENTS FOR PRESERVATIVES

• Prevents the growth of the most likely pathogen
• Soluble enough in water
• Sufficiently undissociated at the pH of the preparation
• Safe and comfortable for the patient at the given concentration
• Amount remains throughout the shelf-life
• Compatible with the other ingredients in the formulation
• Does not adversely affect the container or the closures

➢ pH OF THE PRESERVATIVE
• Maintain undissociation and unionization (Lipid soluble , no charge)
• Chlorobutanol, Benzalkoniumchloride, and phenylmercuricnitrate
➢ MOA OF PRESERVATIVES
• Partial lysis
• Lysis and cytoplasmic leakage
• Irreversible coagulation of cytoplasmic constituents
• Inhibition of cellular metabolism
• Oxidation
• Hydrolysis

PRESERVATIVE CONCENTRATION
Benzoic Acid 0.1–0.2%
Sodium Benzoate 0.1 –0.2%
Alcohol 15 –20%
Phenylmercuricnitrate, acetate 0.002 –0.01%
Phenol 0.1 –0.5%
Cresol 0.1 –0.5%
Chlorobutanol 0.5%
BenzalkoniumCl 0.002 –0.01%
Methylparaben&Propylparaben 0.1 –0.2%