Stability of Drug Preparations

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Stability of Drug Preparations

• Chapter 12

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I. Introduction

• A.Importance
• Stability is the guarantee of safety and
  effectiveness of any preparations
• B.Types of stability studies
• (1)chemical one chemical degradation
• (2)physical one physical appearance
• (3)biological one microorganism pollution
• (4)stability of bioavailability in vivo

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II. Chemical kinetics and drug stability

• A. Orders of reactions
• -dC/dtkCn
• where -dC/dt is the rates of change for the
  reactants k is the reaction rate constant C is
  the concentration n is the order of the reaction
  (n0 zero-order n1 first-order n2
  second-order)

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• Rate Expressions for Zero-, First- and
  Second-Order Reactions
• 
  second-order
• zero-order
  first-order abc0 a?b
  
• Differential rate -dc/dtk
  -dc/dtkc -dc/dtkc2 -dc/dtkcacb
• expression
• Integrated rate k(c0-c)/t
  k(1/t)ln(c0/c) 1/c-1/c0kt
• expression
• t1/2 c0/(2k)
  0.693/k 1/(c0k)
• t0.9 c0/(10k)
  0.105/k 0.11/(c0k)

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• B. The Arrhenius equation
• (1)showing the effect of temperature on the drug
  degradation rate
• (2)integrated kAe-Ea/RT
• logarithmic lgk-Ea/(2.303RT)lgA
• rewritten as ln(k1/k2)(Ea/R)(1/T2-1/T1)
• where Ea is activation energy (a constant and
  independent of temperature) 1 and 2 denote the
  two different temperature conditions k is the
  constant of reaction rate R is gas constant

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• (3)It is possible to conduct kinetic experiments
  at elevated temperature and obtain estimates of
  rate constants at lower temperatures by
  extrapolation of the Arrhenius plot (Accelerated
  stability testing)

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III. Routes by which pharmaceuticals degrade

• A.Chemical degradation routes
• (1)hydrolysis
• (2)oxidation
• (3)dehydration
• (4)isomerization
• (5)incompatibilities
• (6)others hydration, decarboxylation, pyrolysis

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• (1)hydrolysis esters (lactone) and amide
  (lactam)
• methods for delayed hydrolysis
• adjusting pH
• controlling water content
• controlling T
• reduce the solubility of drugs
• solid forms

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• (2)oxidation phenols, enols, unsaturated
  alcohol, arylamine
• mechanism reaction of free radical chains
• induction RH R H (light, heat)
• transmission R O2 RO2
• RO2 RH ROOH
  R
• ROOH RO OH
  (metal ion)
• termination RO2 x inactive
  product
• RO2 RO2
  inactive product

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• methods for delayed oxidation
• reduce oxygen content
• adjusting pH
• reduce metal ion
• lower T
• avoid light

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• B. Physical degradation routes
• (1)vaporization
• (2)aging
• (3)adsorption
• (4)physical instability in heterogeneous systems
  (suspensions, emulsions, creams and ointments)

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IV. Formulation and Environmental factors that
affect reaction rate

• A.pHhydrolysis
• (1)lgk versus pH profiles of different drugs
• (specific acid-base catalysis)

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• (2) method the optimum pH for stabilitypHm
• calculating pHm 1/2pKw-1/2lgkOH-/KH
• through testing a series of solutions with
  different pH valuesaccelerated testinglgkpH
  profilespHm
• (3)general acid-base catalysis
• PBS, ABS
• method change the type or reduce the
  concentration

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• B. solventhydrolysis
• lgklgk8-kZAZB/e
• where k is the reaction rate constant, kis a
  constant, e is the dielectric constant,k8 is the
  reaction rate constant when e 8,ZA and ZB is
  the electric charge of the two ions of A and B,
  respectively

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• C. ion strength
• lgklgk01.02ZAZBI1/2
• where k is the reaction rate constant, k0 is the
  reaction rate constant when I0, ZA?ZB is the
  electric charge of two ions,respectively,I is the
  ion strength

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• D. Surfactants
• enhance or decrease the stability , determined
  by the results of testing
• E. Other excipients
• determined by the results of compatibility
  testing in order to choose correctly

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• F. Temperature
• In general, the higher T is, the faster the
  reaction rate is
• Arrhenius equation
• G. Lightoxidation, photodegradation
• Avoid light during preparation and storage
  package is very important

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• H. Air (oxygen)oxidation
• inert gas (N2, CO2)
• vacuum-packed
• reducing
  agents
• adding antioxidants blockers of oxidation
• synergists
• (note pH value range in which antioxidants are
  suitable to application)
• p272

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• I. Metal ionsinitiate oxidation reactions
• employ raw materials and excipients with higher
  purities
• do not use metal instruments
• use chelating agents (EDTA, citric acid, and
  tartaric acid)
• J. Humidity (water)major determinant of drug
  product in solid dosage forms
• lower RH during preparation
• put drying agents in the package

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• K. Package materials
• glass, plastics, aluminum foil etc
• package evaluation

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V. Stability and degradation kinetics of solid
drug preparations

• A. Properties of stability of solid drug
  preparations
• (1)degradation slowly
• (2)be not uniform
• (3)difference between exterior and interior
• (4)multi-phase systems
• (5)obtain a balance Vant Hoff equation
  lnK-?H/(RT)a
• (6)effect of crystal form

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• B. Chemical degradation kinetics
• (1)nucleation theory
• (2)liquid-layer theory
• (3)topochemical reactions

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VI. Stability testing in the pharmaceutical
industry

• A. Impact factor testing (Stress testing)
• high T (60?, 40 ?)
• high H (25 ?, 755, 905) 10d
• strong light (4500500lx)

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• B. Accelerated testing
• done more frequently and for a shorter duration
• (1)in general, three batches, with package, 402
  ?, RH755, 6m(3m for clinical testing and 6m for
  production)
• (2)specific preparations with various testing
  conditions
• (3)obtain tentative expiry date (shelf time)

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• C. Long-term testing
• (1)in general, three batches, with package, 252
  ?, RH6010, 6m for clinical testing, 12m for
  production and go on
• (2) specific preparations with various testing
  conditions
• (3)obtain definitive expiry date

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• D. Evaluation indices of stability testing for
  various dosage forms
• P279

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• F. Classical isothermal method--done in research
• (1)pre-testing to determine Ts and sampling
  time determine analysis methods
• (2)put samples at predetermined Ts, take a sample
  at predetermined times (t), and determine the
  drug concentrations
• (3)obtain profiles of C t, and determine the
  reaction order (lgCt linearity, first-order)
• (4)according to the equation k(1/t)ln(C0/C),
  obtain k at different Ts
• (5)according to Arrhenius equation
• lgk-Ea/(2.303RT)lgA, obtain profiles of lgkT
• (6)calculate t0.9, k25 ?, Ea , lgA

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• G. Stability testing in new medicine development
• (1)raw materials
• (2)stability in formulation and preparation
  process study
• (3)stability of package materials
• (4)accelerated and long-term testing of
  preparations
• (5)stability after marketing
• (6)stability testing for any change in
  formulation, preparation process or package