PHARMACEUTICS
Hydrolysis (solvolysis process):(drug) molecules interact with water molecule to yield breakdown product. - susceptible to the hydrolytic process: esters, substituted amides, lactones, and lactams
OXIDATION: Loss of electrons from an atom or molecule;
- involves free radicals (molecules or atoms containing one or more unpaired electrons).
- destructive to: Aldehydes, Alcohols, Phenols, Sugars, Alkaloids & unsaturated fats & oils.
Q10 METHOD: estimate the shelf life of a product that has been stored or to be stored under a different set of conditions.
pH – major determinant in stability
- optimum stability: pH 5 & 6
- buffering agents increases stability
oxygen sensitive drugs
* prepared in dry state
*packaged in sealed containers with air replaced by inert gas (Nitrogen, @@carbon dioxide).
* add antioxidants (for stability):
- in aq. Prepns:
@@@@@ Na2SO3, NaHSO3, H3PO2, ascorbic acid.
- in oleaginous/unctous prepns:
@@ alpha tocopherol, butylhydroxyanisole & ascorbyl palmitate.
ltrace metals in drug, solvent, container or stopper.Source of difficulty in preparing stable solns
of oxidizable drugs
- eliminated by:
*purification of source of contaminant.
@@@@ *complexing or binding metal by using specialized agents (chelating agents- Ca disod edetate & EDTA).
Light
- catalyst to OXIDATION reactions.
- prepns packaged in light resistant or opaque containers.
In summary : easily oxidizable drugsmay be stabilized in formulation by:
selective exclusion from the system of:
oxygen oxidizing agents trace metals light heat other chemical catalysis.
Add to create and maintain a favorable pH: antioxidants, chelating agents,buffering agents.
Other destructive process in pharmaceutical preparations:
Polymerization:- reaction between two or more identical molecules with resultant formation of new & generally larger molecule (formaldhyde).
Process where one or more active chemical groups removed:Chemical decarboxylation,deamination.
Decarboxylation: - decomposition of RCOOH & release of CO2.
Deamination: - removal of nitrogen containing group from organic amine (ex. Insulin).
Importance of Drug Stability:
lin preclin. testing and in clinical (human) trials
- for a true and accurate assessment of the drug/drug prod evaluated.
lmarketed drug product
- for the safety and effectiveness when distributed and during the entire course of its shelf-life and use
Drug instability detected:
Change in: physical appearance, color, odor, taste or texture of the formulation.
Scientific data pertaining to the stability of a formulation:
lleads to:
*prediction of the expected shelf-life of the proposed product.
@@@@@*redesign of the drug (to more stable SALT or ESTER form).
*reformulation of the dosage form.
Accelerated stability testing:
Use of exaggerated conditions of temp., humidity, light & others
Accelerated temp.
- @@@@@ 6 mons study at 40 o C with 75% relative humidity.
Short tem accelerated studies
Determines most stable of the proposed formulations for a drug product
lesser temp and humidity;@@@@30oC and 60% humidity.
Long term stability studies:
Product is subjected to different climatic zones (temp. & humidity)nationally & internationally.
Predicted from the data generated from continuing stability studies
@@@@@12 months minimum and conducted at 25 o C +/- 2oC and at a relative humidity of 60% +/- 5%.
Tests performed depending on the intended use and type of container:
physicochem. tests
llight-transmission tests for glass or plastic
ldrug compatibility
leaching and or migration tests,
vapor-transmission test for plastics, moisture barrier tests, toxicity studies for plastics,
valve, actuator, metered-dose, partical size, spray characteristics, leak testing for aerosols,
sterility and permeation tests for parenteral containers
drug stability for all packaging
CLASSIFICATION OF CONTAINERS BY THE USP according to their ability to protect their contents from external conditions:
HERMETIC container:
- impervious/resistant to air or any other gas under the ordinary or customary conditions of handling, shipment, storage, and distribution.
- those sterile are generally used to hold prepns intended for @@injection or parenteral adm.
SINGLE-dose container
- quantity of drug contained is intended as a single dose and when opened cannot be resealed with assurance that sterility has been maintained
- includes fusion-sealed ampules, pre-filled syringes and @@cartridges.
Single-unit packages:
convenient & sanitary means of maintaining and utilizing the medication
ADVANTAGES:
*positive ID of each dosage unit and reduction of medication errors.
*reduced contamination of the drug due to its protective wrapping.
*reduced dispensing time.
*greater ease of inventory control in the pharmacy or nursing station.
*elimination of waste through better medication management with less discarded medication.
Packaging materials: - may be combinations of paper, foil, plastics or @@@@CELLOPHANE.
Packaging of solid dosage forms in:
*clear plastic or aluminum blister wells
- most popular method of single-unit packaging.
Light resistant containers:
Required by many pharmaceutical prods to protect them from photochem. deterioration
@@AMBER or light resistant opaque plastic will reduce light transmission sufficiently to protect a light-sensitive pharmaceutical.
UV absorbers may be added to plastic to decrease the transmission of @@@short UV rays.
Must meet the USP stds w/c define the acceptable @@@@@@@limits of light transmission at any wavelength of light between 290 and 450 nm.
Classification of glass used in packaging pharmaceuticals depending upon the chem.. constitution of the glass and its ability to resist deterioration:
Type I highly resistant, BOROSILICATE glass.
Type II treated SODA-LIME glass.
Type III SODA-LIME glass.
NP gen. purpose soda-lime glass.
Types I, II & III for parenteral prods.
Type NP – for non-parenteral.
Newer plastic materials used:
PET – polyethylene terephthalate
Amorphous PET (APET)
PET glycol (PETG)
APET & PETG
- excellent transparency, luster and can be sterilized with @@@@GAMMA radiation.
Problems encountered in the use of plastics in packaging:
LEACHING: of the constituents of the container to the internal contents.
ABSORPTION: of drugs from the contents to the container.
TRANSMISSION: of light through the container.
ALTERATION: of the container upon storage.
Properties of plastics may be altered:
ADDITION of: plasticizers, stabilizers, antioxidants, antistatic agts, antimold agts, colorants, and others
Drug subs’s subjected to oxidative degradation
- may undergo a greater degree of degradation when packaged in PLASTICS as compared to glass.
LEACHING:
Movement of components of a container into the contents
Cpds leached from the plastic containers:Polymer additives as the plasticizers, stabilizers or antioxidants.
occurs when liq. or semi-solid dosage forms are packaged in plastic.
Little leaching occurs for tabs or caps packaged in plastic
lInfluenced by:
*temp *excessive agitation of the filled container.
*solubilizing effect of liq. contents on one or more of the polymer additives.
Soft-walled plastic containers of @@@@@PVC – polyvinyl Cl
- used to package IV solns and blood for transfusion.
SORPTION:
Binding of molecules to polymer materials
Absorption and adsorption are considered occurs through chem. or phy. means due to:
*chem.. structure of the SOLUTE molecules.
*phy.and chem. properties of the polymer
Occurs with active pharmacologic agts or with pharmaceu. excipients thus, ings must be examined in the proposed plastic packaging to determine its tendency.
Terms employed for the desired conditions as defined by the USP:
COLD
- any temp not exceeding 8oC (46oF).
- a refrigerator is a cold place where the temp. is maintained bet. 2o and 8oC (36o and 46oF).
COOL
- any temp bet. 8o and 15oC (46o and 59oF).
ROOM Temp.
- temp prevailing in a working area.
- 20o to 25oC (68oF to 77oF) but also allows for temp variations @@@ bet 15o and 30oC (59o and 86oF) experienced in pharmacies, hospitals, and drug warehouses.
Warm:- any temp bet 30o and 40oC (86o and 104oF).
Excessive Heat:-any temp above 40oC (104oF).
Stability Testing:
Signs of degradation of the specific dosage forms must be observed and reported.
TABLETS: Apperance (cracking, chipping, mottling), friability, hardness, color.
CAPSULES: Moisture tackiness, color appearance, shape, brittleness and dissolution.
ORAL Solutions and SUSPENSIONS: Appearance, precipitation, pH, color, odor,@@@DISPERSIBILITY (suspension) and clarity (solutions).
FDA guidelines on stability for extemporaneous compounding:
Nonaqueous liquids & solid formulations
(source of active ingredient)’s
- @@@@@not later than 25% of the time remaining until the product’s expiration date or 6 months, whichever is earlier.
Nonaqueous liqs & solid formulations in w/c USP or NF substance (source of ing)
-@@@@ beyond-use not later than 14 days in storage at cold temperatures.
Other formulations beyond-use date of the intended duration of therapy or 30 days whichever is earlier.
Pharmaceutical Ingredients and Excipients:
Definition of terms
SOLVENTS: are used to dissolve the drug substance.
FLAVOURS and sweeteners are used to make the product more palatable
COLORANTS are added to enhance appeal.
PRESERVATIVES may be added to prevent microbial growth.
STABILIZERS (antioxidants and chelating) - to prevent decomposition.
DILUENTS or fillers - to increase the bulk of the formulation.
BINDERS– to cause adhesion of the powdered drug and pharmaceutical substances.
ANTIADHERENTS or lubricants to assist smooth tablet information.
DISIINTEGRATING AGENTS:Promote tablet break up after administration and coatings to improve stability, control disintegration or enhance appearance.
Sweetening Pharmaceuticals :
USED in foods and pharmaceuticals:
*sucrose
*artificial sweetening agents
SWEETENING PHARMACEUTICALS
- mask unwanted taste
- commonly used - sucrose
-Delaney Clause: no new food additives may be used if animal studies/appropriate tests showed that it caused cancer.
SACCHARIN & CYCLAMATE - used in foods
-“generally recognized as safe” (before the amendment’s passage).
- use on rats: developed incidence of bladder tumors (cancer).
- continued availability but warning labels be used.
@@@@@@@CYCLAMATES (banned) - possible CARCINOGENICITY, genetic damage, testicular atrophy.
ASPARTAME –
- 1st artificial sweetener (1958 amendment).
w/ requirement for pre-marketing proof of safety.
@ACESULFAME POTASSIUM (non nutritive sweetener).
- structurally similar to SACCHARIN (USP approved)
-@@@@@130 times as sweet as sucrose, excreted unchanged in the urine;
- more stable than ASPARTAME.
@STEVIA (Stevia rebaudiana Bertoni)
– new sweetening agent: natural, nontoxic, safe,
@@@@@30x sweeter than cane sugar/sucrose
Coloring Pharmaceuticals:
90% of the dyes used in the products - synthesized from derivative of benzene@@@@ (aniline).
FDA - regulates use color additives in foods, drugs, and cosmetics (Federal Food, Drug, and Cosmetic Act of 1938)
- FD&C color additives - foods, drugs, and cosmetics.
- D&C color additives - drugs, some in cosmetics & medical devices.
- external D&C color additives - restricted to external parts of the body (not including the lips and other parts that are covered by mucous membrane).
Factors in selecting dyes:
Solubility of prospective dye.
pH & pH stability of the preparation to be colored.
Dyes must be PHOTOSTABLE.
Sterilization and Preservation:
some types of pharmaceutical products
(ex. Ophthalmic and injectable preparations)
- sterilized by physical methods :
@@@@@*autoclaving (20min at 15 lb. press. & 121°C, dry heat at 180°C for 1 hr).
*bacterial filtration.
lprevent microbial growth:
*15% alcohol in acid media
*18% alcohol in alkaline media.
@@@@@Alcohol-containing pharmaceuticals (elixirs, spirits, and tinctures) - self sterilizing and do not require additional preservation.
Mode of action: Mechanisms preservative interfere with microbial growth, multiplications, and metabolism:
1. Modifications of cell membrane permeability and leakage of cell constituents (partial lysis).
2. Lysis and cytoplasmic leakage.
3. Irreversible coagulation of cytoplasmic constituents.
4. Inhibition of cellular metabolism by interfering with enzyme systems/inhibition of cell wall synthesis.
5. Oxidation of cellular constituents.
6. Hydrolysis.
PRESERVATIVES:
- suitable substances added to enhance its permanency or usefulness.
- examples: commonly employed:
Benzoic acid,Sodium benzoate,Alcohol,Phenylmercuric nitrate and acetate,Phenol, Benzalkonium chloride.
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