Transcript PowerPoint Template

Pre-formulation
Dr. Zahra Hesari
Pharm D, PhD of Pharmaceutics
Session 3
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Guilan university of Medical Sciences, Faculty of Pharmacy
Review
potency
Proteins
Organic Salts
(Dose)
Membrane
permeability
Solid dosage form
excipients
Organic
esters
Hydrates &
solvates
LogP
pKa
Drug and Drug Product Stability
• Drug samples of known purity
• Stability studies in the preformulation phase:
– Solid-state stability of the drug alone
– Solution-phase stability
– Stability in the presence of expected excipients
 Initial investigation: drug’s
chemical structure
 Drug substances (Chemically):
alcohols, phenols, aldehydes,
ketones, esters, ethers, acids, salts,
alkaloids, glycosides
Drug Stability
Mechanisms of Degradation
• Most frequently chemical destructive processes
– Hydrolysis
– Oxidation
• Hydrolysis
– Drug molecules interact with water molecules to yield breakdown
products
– Great number of drugs are esters or contain such other groupings as
substituted amides, lactones, and lactams
•
Oxidation
– Aldehydes, alcohols, phenols, sugars, alkaloids, and unsaturated fats
and oils
– Loss of electron, increase in the positive valence, loss of hydrogen
– Free chemical radicals
– Autoxidations: (atmospheric oxygen- chain reaction)
Kinetics and Shelf Life
•
Stability definition
•
Stability concern types:
1.
2.
3.
4.
5.
•
Chemical stability
–
–
–
•
Chemical
Physical
Microbiologic
Therapeutic
Toxicologic
Storage conditions
Proper container
Anticipating interactions when mixing drugs and dosage forms
Stability and expiration dating are based on reaction kinetics
Reaction kinetic
Study of rate of chemical change
This rate is influenced by concentration of reactants, products and
solvent, pressure and temperature.
Rate Reactions
• Reaction rate is a description of the drug concentration with
respect to time.
• Most commonly in pharmacy
– Zero-order reaction
– First-order reactions
Q10 Method of Shelf Life Estimation
Estimate shelf life for a product that has been stored or is going to
be stored under a different set of conditions
Enhancing Stability of Drug Products
• Incorporation of excipients
– Increase the stability of the drug substance
• Hydrolysis:
•
Hydrolysis & Oxidation
reduction or elimination of water:
waterproof protective coating over tablets
keeping the drug in a tightly closed container
substitute liquids such as glycerin, propylene
glycol, and alcohol
Anhydrous vegetable oil in injectable products
Suspending in a nonaqueous vehicle rather
than dissolving in an aqueous solvent
Dry form for reconstitution (sp antibiotics)
•
•
Refrigeration
pH (5-6), buffering agents
Enhancing Stability of Drug Products
Oxidation
•
•
Humidity in presence of oxygen or light
Combination with other chemicals
•
•
Alteration in the color, precipitation or a change in odor
Antioxidants: providing electrons and hydrogen atoms
Aqueous preparations:
 sodium sulfite (Na2SO3, at high pH)
Oleaginous (oily or unctuous)
 sodium bisulfite (NaHSO3, at
Preparations:
intermediate pH)
 sodium metabisulfite (Na2S2O5, at
low pH)
•
hypophosphorous acid (H3PO2)
•
ascorbic acid
 alpha-tocopherol,
 Butyl hydroxy anisole
 ascorbyl palmitate
Sulfites
• Preservative
–
–
–
Injectable drugs, such as antibiotics and local anesthetics
inhalants and ophthalmic preparations
few oral drugs
• FDA labeling regulations
–
No generally suitable
substitutes for sulfites
0.2% of the population who are subject to allergic reactions
o Food products
potassium bisulfite, potassium metabisulfite, sodium bisulfite, sodium metabisulfite,
sodium sulfite, and sulfur dioxide.
 Antioxidant + other pharmaceutical additives
 Antioxidant + drug substance
 oxygen-free atmosphere during preparation and storage
Oxidation
• Trace metals
– Purification of the source
– Chelating agents: calcium disodium edetate and EDTA
• Light (catalyst)
– packaging in light-resistant or opaque containers
• Temperature
– Keep in cool place
• pH
– Most favorable for each
preparation
• Potassium Iodide Oral Solution, USP
– Yellow to-brown discoloration
– light-resistant containers
– addition of 0.5 mg of sodium thiosulfate for each gram of KI.
Formulation pharmacist may stabilize the preparation by the
selective exclusion from the system of oxygen, oxidizing agents,
trace metals, light, heat, and other chemical catalysts to the
oxidation process. Antioxidants, chelating agents, and buffering
agents may be added to create and maintain a favorable pH.
Other less frequent destructive processes include polymerization,
chemical decarboxylation, and deamination.
Drug-Excipient Compatibility
• Stress condition
– Guideline of accelerated stability studies
– Temp, pH, light, moisture, agitation, gravity, packaging, method
of manufacture
• Experimental studies:
– Mixing drug with excipients
– Aqueous suspension of Drug-Excipients
– Factorial design
• water addition: yes/no,
• Temp: 25 or 40 ‘C
• Time: 1 or 4 week
– High temp & high humidity
– Intact drug & degradation product are measured
– Drug content, color, taste, related substances
• Advanced analytical instrumentation
–
–
–
–
Detect low levels of degradation products (less than 2%)
Thermal analysis (DTA, DSC)
Chromatographic methods (HPLC, LC/MS)
Diffuse reflectance spectroscopy (DRS)
Stability Testing
• Pharmaceutical components and finished products
• FDA’s GMP and ICH guideline:
 “Stability Testing of New Drug Substances and Products”
 “Quality of Biotechnological Products: Stability Testing of
Biotechnology/Biological Drug Products”
 “Photostability Testing of New Drug Substances and Products”
 “Stability Testing of New Dosage Forms”
 Drug stability is important during preclinical testing and in clinical
(human) trials
 For marketed drug product is vital during shelf life
• Stability assessment before approval for marketing:
– Influence of pharmaceutical ingredients
– Influence of the container and closure
– The manufacturing and processing conditions (e.g., heat)
– Packaging components
– Conditions of storage
– Anticipated conditions of shipping, temperature, light, and humidity
– Anticipated duration and conditions of pharmacy shelf life and patient
use.
 In-process stability testing
 Packaging features
Extemporaneous compounded formulations
• USP guidelines on stability:
1. nonaqueous liquids and solid formulations in which the
manufactured drug is the source of the active ingredient, not
later than 25% of the time remaining until the product’s
expiration date or 6 months, whichever is earlier.
2. nonaqueous liquids and solid formulations in which a USP or
National Formulary (NF) substance is the source of active
ingredient, a beyond-use date of 6 months.
3. watercontaining formulations prepared from ingredients in
solid form, a beyond-use date not later than 14 days in
storage at cold temperatures.
4. all other formulations, a beyond-use date of the intended
duration of therapy or 30 days, whichever is earlier.
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