DDS Lecture 6 Content

Liquid dosage form categories

• non-sterile (aqueous or non-aqueous)

• sterile (free from microbes, aseptic, can be injected)

Non-Sterile Aqueous Liquid dosage forms

• suspensions

• emulsions

• solutions

• syrups

• elixirs

• tinctures

• topical sprays and solutions

• aromatic waters

• douches

• enemas

• gargles

• mouthwash

Non-sterile, non-aqueous liquid dosage forms

• liniments

• colloidions

• extracts

Syrup

• concentrated aqueous preparations of sugar or sugar substitute with or without flavoring agents and medicinal substances

• syrups containing flavoring agents but not medicinal substances = non-medicated or flavored vehicles/syrups

• most contain:

  • purified water

  • medicinal agents (if applicable)

  • sugar (usually sucrose): provide sweetness/viscosity

  • antimicrobial preservatives

  • flavorants

  • colorants

Meperidine HCl

• syrup

• Demerol Syrup (Sanofi-Synthelabo)

• 50 mg/5mL

• opioid analgesic for the relief of moderate to severe pain, adjunct to general anesthesia

Antihistimine Syrup formula

• chorpheniramine maleate = active ingredient (antihistimine)

• glycerin = thickening agent, sweetening agent, levigating/wetting agent

• syrup = sweeting agent, solvent

• Sorbitol solution = sweetening agent

• Sodium benzoate = preservative

• Alcohol = solvent, preservative

• Color and flavor = coloring, flavoring agent

• purified water = solvent

Elixirs

• clear, sweetened hydroalcoholic solutions intended for oral use and are usually flavored to enhance their palatability

• non-medicated elixirs = vehicles

• Medicated elixirs = therapeutic effect of the medicinal substances they contain

• less sweet, less viscous than syrups

  • lower proportion of sugar

• less effective than syrups in masking taste

• hydroalcoholic character makes them better able than aqueous syrups to maintain both water-soluble and alcohol soluble components in solution

• preferred over syrups because of stable characteristics and easy of solution

Phenobarbital Elixir

• phenobarbital

• orange oil

• propylene glycol

• alcohol

• sorbitol solution

• color

• purified water

Absorption in solutions vs tablet

• drug absorption from solution dosage form is higher than in tablet form

• must use lower concentrations of solution to achieve same serum concentration in body

• solutions have higher bioavailability compared to tablets

• Cmax= maximum concentration

• Tmax= time required for maximum concentration (~2 hours on graph)

Tinctures

• alcoholic or hydroalcoholic solutions prepared from vegetable materials or from chemical substances

• vary in preparation, strength, alcoholic content, intended use

• when prepared from chemical substances (iodine, thimerosal), prepared by simple solution of chemical agent in solvent

Examples of tinctures applies to skin

• Green soap tincture

  • 65% API

  • alcoholic

  • detergent

• iodine tinctures

  • 2% API

  • hydroalcoholic

  • topical anti-infective

• compound benzoin tincture

  • alcoholic

  • topical protectant

• podophyllin

  • benzoin tincture

  • removal of genital warts

Vaginal Douches

• irrigation cleansing of vagina

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• solutions may be prepared from powders or from liquid solutions/concentrates

• in using liquid concentrates, patient is instructed to add the prescribed amount of concentrate (usually teaspoonful or capful) to certain amont of warm water (qt)

Components of Douche powders

• Boric acid

• Astringents

• Antimicrobials

• Quaternary ammonium compounds

• Detergents

• Salts

• Aromatics

Retension Enemas

• administered rectally for local effects or systemic adsorption

• minimizes undesirable gastrointestinal reaction

• clinically effective blood levels of agents usually obtained within 30 minutes following rectal instillation

Evacuation Enemas

• cleanse the bowel

• commercially available in disposable plastic squeeze bottles containing pre-measured amount of enema solution

• instruction from pharmacist is advantageous to ensure patient correctly uses products

• patient should be advised to gently insert the tip of the product with steady pressure and be told that it is not necessary to squeeze all of the contents out of the disposable plastic bottle

• patient should be told that product will probably work within 5-10 min

Hydrocortisone

• corticosteroids administered as retention enemas or continuous drip as adjunctive treatment of ulcerative colitis

• administered rectally for local effects

Aminophylline

• administered rectally for systemic absorption

• minimizes undesirable GI reactions associated with oral therapy

Enema solution agents

• sodium phosphate and sodium biphosphate

• glycerin and docusate potassium

• light mineral oil

Liniments

• alcoholic or oleaginous solutions or emulsions of various medicinal substances intended to be rubbed on the skin

• liniments with alcoholic or hydroalcoholic vehicle are useful when rubefacient (produces redness of skin, used to treat pain), counterirritant, or penetrating action is desired

• Oleaginous liniments employed when massage is required

Collodoins

• liquid preparations composed of pyroxylin dissolved in a solvent mixture usually composed of alcohol and ether with or without added medicinal substances

Pyroxylin

• nitrocellulose, soluble gun cotton, collodion cotton

• obtained by mixture of nitric acid and sulfuric acids on cotton

• consists chiefly of cellulose tetranitrate

• appearance of raw cotton when dry but harsh to touch

• available commercially moistened with ~30% alcohol

Solvents for liquid preparations

• alcohol, ethyl alcohol, ethanol

• diluted alcohol (50% alcohol, 50% water)

• alcohol, rubbing (only topical use)

• glycerin

• isopropyl rubbing alcohol (only topical)

• propylene glycol

• purified water

Alcohol

• most useful solvent in pharmacy other than water

• used as primary solvent for many organic compounds

• forms hydroalcoholic mixture with water that dissolves both alcohol-soluble and water-soluble substances

  • useful in extraction of active constituents from crude drugs

  • by varying proportion of two agents, active constituents may be selectively dissolved and extracted or allowed to remain behind according to solubility

• Alcohol, USP: 94.9-96% C2H5OH by volume when determined at 15.56 degrees C

• Dehydrated Alcohol, USP

  • absolute alcohol

  • not less than 99.5% C2H5OH by volume

  • used when essentially water-free alcohol desired

Diluted Alcohol, NF

• prepared by mixing equal volumes of alcohol, USP and purified water (USP)

• final volume is generally about 3% less than expected because liquids contract upon mixing

  • 50ml alcohol + 50 ml water ~97ml diluted alcohol

  • concentration of diluted alcohol is slightly greater than half of concentrate

• useful hydroalcoholic solvent in various pharmaceutical processes and preparations

Rubbing alcohol

• 70% ethyl alcohol by volume

• 30%: water, denaturants, color, additives, perfume oils, stabilizers

Glycerin, USP

• aka Glycerol

• clear, syrupy liquid

• sweet taste

• miscible with water and alcohol

• comparable solvent with alcohol, but solutes are slowly soluble because of viscosity (rendered less viscous by heating)

• preservative qualities

• often used as stabilizer and auxiliary solvent in conjunction with water or alcohol

• used in many internal preparations

Isopropyl Rubbing Alcohol

• 70% isopropyl alcohol by volume

• 30% water, color additives, stabilizers, perfume oils

• used externally as rubefacient and soothing rub

• vehicle for topical products

Propylene Glycol, USP

• viscous

• miscible with water and alcohol

• useful solvent

• substitution for glycerin

Purified Water, USP

• prepared by distillation, ion exchange, or reverse osmosis

Naturally occurring water

• exerts solvent effect on most substances it contacts

• impure

• contains dissolved inorganic salts (Na, K, Ca, Mg, Fe, Cl, sulfates, bicarbonates), dissolved and undissolved organic matter, microbes

Oral solutions and preparations for oral solution

• dry mixtures for solution

• oral solutions

• oral rehydration solutions

• oral colonic lavage solution

• magnesium citrate oral solution

• sodium citrate and citric acid oral solution

Very Soluble

less than 1 part solvent required for 1 part solute

Freely soluble

1-10 parts solvent required for 1 part solute

Soluble

10-30 parts solvent required for 1 part solute

Sparingly Soluble

30-100 parts solvent required for 1 part solute

Slightly Soluble

100-1000 parts solvent required for 1 part solute

Very slightly soluble

1000-10,000 parts solvent required for 1 part solute

Practially insoluble or insoluble

10,000+ parts solvent required for 1 part solute

Order of solubility descriptions

• very soluble

• freely soluble

• soluble

• sparingly soluble

• slightly soluble

• very slightly soluble

• practically insoluble/insoluble

Order of solubility parts of solvent required for 1 part solute

• <1

• 1-10

• 10-30

• 30-100

• 100-1000

• 1000-10,000

• 10,000+

If given that water solubility of atropine is 455, it means that

455 mL of water required to dissolve 1 g of atropine

Considerations for making solutions

• do not quantity sufficient with stirring rod in graduate

• dissolve salts in a minimum amount of water before adding to viscous vehicle

• constant mixing when adding two liquids together

• minimum measurable quantity in graduate cylinder

• insoluble materials: levigate (grind to fine smooth powder while in moist condition)

Percent weight in volume

• %w/v

• grams of constituent in 100 ml preparation

Percent volume in volume

• %v/v

• mL constituent in 100 mL of preparation

Percent weight in weight

• % w/w

• grams constituent in 100g preparation

Ratio strength: weight in volume

• a:b w/v

• grams of constituent in stated ml’s of preparation

Ratio strength: volume in volume

• a:b v/v

• mls of constituent in stated mls of preparation

Ratio strength: weight in weight

• a:b w/w

• grams of constituent in stated number of grams

Liquid dosage forms can be sterile of non-sterile (T/F)

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Stability considerations in the preparations of oral liquid dosage forms

• stability unfavorable for only 6/83 dosage forms (small %)

  • small % have stability issues

• minimum risk associated with dosage forms and pharmacists taking cognizance of various factors:

  • drug stability (less than 10% drug loss)

  • mechanisms

  • routes of degradation

    • hydrolysis

    • oxidation

    • microbial

  • potential interactions with excipients in the tablets and/or capsules utilized in the formulation

Major issue with liquid dosage forms

• stability

• stability changes with temperature, container choice, light exposure

Management of oral liquid preparations in practice

1. Commercial product

2. If no suitable commercial product, consider therapeutic alternative that is available in suitable dosage form (other commercially available drug in same class)

3. Pharmacopoeial formula

   1. consult USP

   2. must be used if formulary requires API in powder form (as opposed to crushing tablet)

   3. if API not available in pure form, literature search for a suitable stability-indicating formula using tablets or capsules for API must be sought

4. Stability-indicating formula

   1. literature

   2. get from other vendors (Allen’s Compounded Formulations, Nahata and Hipple’s Pediatric Drug Formulations, Trissel’s stability of compounded formulations)

5. Design formula using scientific principles

   1. if not in literature, must use science principles

   2. consider potential degradation of API, storage /packaging considerations, assigning suitable shelf-life, interactions between excipients and API (esp if tablets or capsules used as API)

6. Tablet dispersion method

   1. crush tablet, dissolve in water

Preservative selection

• must not adversely affect container, closure

• must be soluble in water

• must be non-irritating, non-toxic

• concentration of preservative must not be too high (harmful to patients)

• concentration of preservative must not be too low (ineffective)

• must consider pH of solution (proportion of preservative remaining undissociated at pH of preparation makes it capable of penetrating microorganisms)

• ex. 15% v/v alcohol will prevent microbial growth in acidic medium (18% v/v in alkaline)

Benzoic acid, boric acid, p-hydroxy benzoates

• preservative

• mode of action: denatures proteins

• widely used

Phenols, chlorinated phenolic compounds

• preservative

• mode of action: lytic and denaturation action on cytoplasmic membranes, oxidation of enzymes

Alcohols

• preservative

• mode of action: lytic denaturation action on membranes

Quaternary compounds

• preservative

• lytic action on membranes

Mercurials

• preservative

• mode of action: denaturation of enzymes by combining with thiol

Common Preservatives

• Benzalkonium chloride

• Glycerin

• Methyl Paraben

• Benzoic acid

• sodium benzoate

Pharmaceutical preservatives have different modes of action such as denaturation of proteins or membrane, combine with -SH groups and protect from light (T/F)

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Major criterion in drug design and evaluation

stability

Rates and orders of reactions

• velocity with which reaction occurs

• depend on reactant concentration, temp, pH

Drugs most frequently undergo degradation by either oxidation or hydrolysis (T/F)

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Degradation by Hydrolysis

• molecules interact with water to yield breakdown products

• Aspirin (Acetylsalicylic acid) + water → salicylic acid + acetic acid

• causes drug decomposition for drugs containing: amides, lactones, lactams

Degradation by Oxidation

• loss of electrons for a molecule

• each electron lost is accepted by some other molecule, reducing recipient

• many pharmaceutical have tendency to undergo auto oxidation: atmospheric oxidation proceeds slowly at first, then rapidly

• destroys aldehydes, alcohols, phenols, sugars, alkaloids, unsaturated fatty acids, oils

• for inorganix compounds: ferrous (Fe2+) to ferric (Fe3+)

Handbook of Pharmaceutical Excipients

Food and Chemical Codex

• 2 books

• monographs of excipients

• each monograph includes:

  • non-proprietary

  • chemical

  • commercial names

  • empirical and chemical formula

  • physical properties

  • incompatibilities and interactions with other drugs and excipients

  • regulatory status

  • applications in pharmaceutical formulation or technology

Buffering Agent

• used to resist change in pH on dilution or addition of acid or alkali

• ex. potassium monophosphate, potassium phosphate monobasic, sodium acetate

Chelating agent

• substances that form stable water-soluble complexes (chelates) with metals

• aka sequestering agents

• ex. Na2-EDTA, eidetic acid

Humenctant

• used to prevent drying of preparations, particularly ointments and creams

• ex. glycerin, propylene glycol, sorbitol

Litigating agent

• liquid used as intervening agent to reduce particle size of powder by grinding, usually in mortar

• ex. mineral oil, glycerin propylene glycol

Ointment base

• semisolid vehicle for medicated ointments

• ex. lanolin, petrolatum

Stiffening agent

• used to increase thickness or hardness of a preparation, usually ointment

• ex. cetyl alcohol, paraffin, stearyl alcohol

Suspending agent

• viscosity increasing agent used to reduce sedimentation rate of particles in a vehicle in which they are not soluble

• ex. agar, bentonite, carbomer,tragacanth veegum

Vehicle

carrying agent used in formulating a variety of liquids for oral and parenteral administration

Degradation tests/inspections for topical creams, ointments, lotions, solutions, gels

• appearance

• color

• homogeneity

• odor

• pH

• resuspendability

• consistency

• particle size distribution

• strength

• weight loss

Degradation tests or inspection for emulsions

• appearance (phase separation)

• color

• odor

• pH

• viscosity

Pharmaceutical ingredients have a specific role in the preparation, however, some ingredients have multiple uses in the preparation (Glycerin, propylene glycol) T/F

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Gargles

• aqueous solutions containing antiseptics, antibiotics, anesthetics

• local effect for pharynx, nasopharynx, by forcing air from lungs through the gargle held in throat

• gargle is expectorated

• sometimes diluted before use

Mouthwash

• aqueous solutions often in concentrated form

• therapeutic and non-therapeutic

• recent uses in stomatitis (painful side effect of chemotherapy)

  • combination with antihistimines, hydrocortisone, nystatin, tetracyline

• suspension, powder, syrup, solutions

Mouthwash composition

• Alcohol: flavor, sharpness, mask unpleasant taste, solubilizer for flavoring agents

• Glycerin, sorbitol: humectant

• surfactant: aid solubilization

• flavor

• color

Oleo vitamins

• fish liver oils diluted with edible oils (vegetable oils)

• vitamin A and D

• Vitamin D = ergocalciferol

• synthetic vitamin A

• unstable preparations = use tight container

• protect from light and air

Categories of medicated syrups

• analgesics

• bronchodilator

• cholinergic

Special Solutions and Suspensions

• applied topically to eye, nose, ear

• suspensions, solutions, gels, ointments, drug containing inserts

Ophthalmic drug delivery

• treat surface or intraocular infections/conditions

• volume of tear film in eye varies between 7-8 mcL

• limited capacity to retain fluid

• single drop of ophthalmic solution contains 50 mcL (most fluid is lost)

Pharmacological categories of topical Ophthammic drugs

• anesthetics

  • provide temporary relief for ophthalmic trauma

• antibiotic and antimicrobial agents

  • combat ophthalmic infections

• antifungal agents

  • fungal keratitis

• antiinflammatory

  • allergic cognitivists

• antiviral

  • herpes

Pharmaceutical Requirements for opthalmic drugs

• sterility and preservation

• isotonicity

  • osmotic pressure similar to surrounding fluid

  • tears, blood have osmotic pressure of 0.9% solution of sodium chloride

• buffering

• viscosity and thickening agents

Opthalmic sterility

• must be sterile

• benzalkonium chloride or chlorobutanol used as antimicrobial agent

Nasal Preparations

• most preparations intended for intranasal use contain adrenergic agents

  • decongestant

  • nasal drops/sprays

Inhalation Solutions

• drugs or solutions of drugs administered by nasal or respiratory route

• local action on bronchial tree or systemic effects through absorption from lungs

• ex. isoproterenol inhalation solution

Nasal route for systemic effect

• when you ned route that is neither oral or parenteral

• ex. synthetic, biologically active peptides/polypeptides (insulin)

Inhalants

• designed for drug to be carried into the bronchial/respiratory tree of patient

• mist reaches the affected area and provides relief

• used for bronchial, nasal congestion

Nebulization

• gives sufficient fine particles, droplets, uniform in size

• attached to face mask

• intermittent positive pressure breathing machine

• metered dose inhalers

The otic, nasal, and ophthalmic drug delivery products consisting of solutions and suspensions are considered as special drug delivery systems (T/F)

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Otic preparations

• ear or aural preparations

• solutions, suspensions, ointments

• curumen removing

  • removes ear wax

• anti-infective

  • fungal/other infections

• anti-inflammatory

  • swelling and inflammation

• analgesic

  • relieves symptoms of acute otitis media

Quality control of liquids

• final volume

• appearance

• odor

• clarity

• specific gravity

• pH

• active drug assay

  • determines concentration is correct

• rheological properties/pourability

Quality assessment

• weight/volume

• pH

• specific gravity

• active drug assay

• clarity

• globule size range

• rheological properties/pourability

• physical observation