solid state stabilityanis
TRANSCRIPT
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SOLID STATE STABILITY
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Stabilitas padatan
Fisika Transformasi Polimorfik
Kristalisasi, perubahan bentuk polimorf, interaksidengan eksipien, interaksi dengan lembab,kontaminasi.
KimiaoAkibat perubahan pada intramolekular atau
intermolekular
o Reaksi Hydrolysis, oxidation, photolysis
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Stabilitas fisika
Stability of amorphous form
greatly depends on how is it prepared.
Crystallization above Tg
Presence of residual crystallinity (defect sites)can be source for nucleation
In general, grinding/milling produces least stable
amorphous form
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Stability of the crystalline state Polymorphic transformation and solvation/desolvation
biggest problems
Stability of polymorphic form may depend upon
temperature
Presence of moisture can promote polymorphic and
pseudopolymorphic transformations
Polymorphic and pseudopolymorphic changes are often
observed upon scaling up a process
Stabilitas fisika
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Stability of amorphous formo Reactivity much more likely above Tg
o Above Tg, reactions in the amorphous state may be
thought of as a continuation of reactions in the melt
o Hydroscopic nature can promote hydrolysis reactionso May also be more sensitive to oxidation and
photochemical degradation
o small amounts of amorphous material is the source of
many stability problems observed
Stabilitas kimia
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Stability of the crystalline state Four steps to a solid-state reaction
1. Loosening of molecules at the reaction site- necessary distortion of reaction cavity
2. Molecular change - breaking and formingof chemical bonds
3. Solid-solution formation - reactant andproduct both present in crystal
4. Separation of product - production of new
product crystals Molecular mobilitycan be enhanced by
presence of defect sites Common reactions in the solid state include
hydrolysis, oxidation, and photolysis
Stabilitas kimia
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Stability of the crystalline state
Topochemical postulate :
reactions in crystals occur with a minimum of atomic
and molecular movement
Reaction Kinetic
Reaction kinetics in solid state much morecomplicated than in solution Nucleation-based mechanisms commonly used
Equations Relatingto Decompositionin the Solid State
Stabilitas kimia
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SIMPLEST DECOMPOSITION MODESOF PURE SOLIDS
Solid is placed in a vacuum & exposedby temperatureI Solidsolid + solid
II Solidsolid + liquid
III Solidliquid + liquid
IV Solidsolid + gasV Solidliquid + gas
VI Solidgas + gas
REACTION KINETICS
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Crystalline State and
Polymorphism in Solid Drugs
The chemical stability of solid drugs isaffected by the crystalline state of the
drug.
Drugs in the crystalline state havelower ground-state free energy and
exhibit higher Gand, therefore,
slower reactivity.
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Crystallization of Amorphous
Drugs
Attempts are often made to formulate poorlywater-soluble drugs in their amorphous state,because the solubility of amorphousmaterials is generally higher than that of
crystalline state Because of the lower free energy of the
crystalline state, amorphous substances tendto change to their more thermodynamicallystable crystalline state with time.
Therefore, crystallization of amorphous drugsubstances may occur during long-termstorage and may lead to drastic changes inthe release characteristics of the drug
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P l hi /T i i i
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Polymorphism/Transitions in
Crystalline States
Polymorphs are different crystalline forms ofthe same drug.
Because these forms have different freeenergy or chemical potentials, depending ontemperature conditions, transitions betweenpolymorphs occur.
Polymorphic transitions during storage mayalter critical properties of drugs because thesolubility and dissolution rate of drug
substances generally vary with changes intheir crystalline form.
From a storage perspective, temperature andhumidity affect polymorphic transitions.
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Polymorphism
Many drug substances exhibit polymorphism Each crystalline state has a different ground-
state free-energy level and a differentchemical reactivity
Ex : Solid-state hydrolysis of carbamazepinefrom needle-shaped crystals with a higherCrystalline order is faster than that of beam-shaped and prismatic forms
Reactivity of carbamazepine to light also
depends on the crystalline form of the drug Differences in reactivity among different
crystalline forms have also been reported forphotodegradation of furosemide.
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The stability of drugs in their amorphousform is generally lower than that of drugs
in their crystalline form, because of thehigher free-energy level of theamorphous state.
Decreased chemical stability of solid
drugs brought by mechanical stressessuch as grinding is due to a change incrystalline state
A relationship between the stability andgrinding time was attributed to theincreased solubility
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Effect of grinding time on the degradation of aspirin in
suspension at 40C.
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The chemical stability of solid drugs isalso affected by the crystalline state of
the drug through differences in surface
area. For reactions that proceed on the solid
surface of the drug, an increase in the
surface area can increase the amountof drug participating in the reaction.
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Effect of Moisture and Humidity
on Solid Drugs The effect of moisture and humidity on
the degradation kinetics of ascorbic
acid, thiamine salts,aspirin, vitamin A
and ranitidine hydrochloride has beenreported.
Moisture plays two primary roles in
catalyzing chemical degradation
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mechanism
water participates in the drug degradationprocess itself as a reactant, leading to hydrolysis.degradation rate is directly affected by theconcentrations of water, hydronium ion, orhydroxide ion
water adsorbs onto the drug surface and forms amoisture-sorbed layer in which the drug isdissolved and degraded.
Water adsorption may also change the physicalstate of drugs, thereby affecting their reactivity.
Thus, water affects drug degradation indirectly byproviding a favorable environment fordegradation
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The mechanisms for these effects ofwater are determined by the physical
state of water molecules.
For example, for drugs that formhydrates, water of crystallization is
trapped in the crystals and, generally,
cannot participate in chemicalreactions.
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Water of crystallization can participatein drug degradation when it is releasedfrom the crystalline state by actionssuch as grinding.
This has been reported for thehydrolysis of sodium prasterone sulfateand ampicillin trihydrate.
The degradation rate of ampicillintrihydrate increased with increasinggrinding time
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Effect of grinding on the degradation of ampicillin trihydrate duringstorage at 40C. Grinding time, 0, , 15 min; , 30 min; ,60 min;120min; , 180 min.
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Moisture Adsorption
Moisture adsorption during storage canalso affect the physical stability ofpharmaceuticals, leading to changes insuch properties as appearance and
dissolution rate.Adsorption of moisture is governed by
the physical properties of the drugsubstance and excipients.
For example, the adsorption of moistureby aspirin crystals was enhanced byadding hydrophilic excipients
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Excipients
excipients may participate directly indegradation as reactants, such as additionreactions with drugs.
Excipients may also exhibit catalyzing effects
toward drug degradation (ex. the nucleophiliccatalysis effect of sugars (such as glucoseand sucrose) and amines on the degradationof ester or amide drugs)
Other mechanisms include the effect ofmoisture present in excipients,
the effect of pH changes caused byexcipients
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Eksipient
Beberapa eksipient dilaporkanmeningkatkan kecepatan degradasi
seperti :
mempercepat hidrolisis tabletThiamin HClTalcum :
mempercepat perubahan warnapada tablet yang mengandung
amina dan lactoseMg Stearat :
meningkatkan degradasi tabletaspirin
Asam stearatdan kalsium
suksinat
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Effect o f the Amount o f
Mois ture Present in Excip ien ts Excipients can affect drug stability by being a source ofmoisture.
For example, owing the high moisture content ofpolyvinylpyrrolidone and urea, aspirin hydrolysis wasenhanced in solid dispersions with these excipients
Decreased drug stability caused by excipients havinghigher moisture-containing ability has been reported fortablets of aspirin and ascorbic acids
Degradation of ascorbic acid in the presence of silicagel increased with increasing water content
The higher degradation rate observed in the presence
of silica gel compared to that for ascorbic acid alone atthe same moisture content suggested an acceleratingeffect of silica gel itself or of one of its impurities
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Effec t o f the Phys ical State o f
Water Mo lecu les in Exc ipients water present in excipients exists in various
physical states, being either weakly orstrongly adsorbed to the excipient.
The physical state of water can affect drug
degradation. Excipients having strong water-entrapping
abilities tend to inhibit drug degradation
excipients having higher adsorption energy
decrease water reactivity and therebydecrease the relative hydrolysis rates
Like how antioxidant works
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Other Propert ies o f Exc ipients
Excipients can also affect drug stability by alteringmicroclimate pH.
The surface acidity of excipients has been reported tobe a factor contributing to drug degradation
Lomustine exhibited faster degradation in poly( d,l-lactide) microspheres than in its pure crystalline state
enhanced degradation has been attributed to moleculardispersion of the drug in the microspheres,
the possibility that the terminal carboxylic acid groupsof poly( d,l-lactide) effect micro-pH changes
Enhanced degradation of solid oxazolam in thepresence of microcrystalline cellulose may be attributedto carboxylic acid groups on the cellulose surface
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Miscellaneous Factors
Excipients affect drug degradation via variousmechanisms other than pH changes.
The effect of stearate on the degradation ofaspirin has been explained by a change in
melting behavior rather than pH changes Dye excipients may enhance oxidation and
photodegradation of drugs by producingsinglet oxygen that participates in chain
reactions. Ex: enhancement of the oxidation of
phenylbutazone and ascorbic acid by dyeexcipients.
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Miscellaneous Factors
irradiation is employed for thesterilization of some pharmaceutical
products, and its effect on drug
stability should therefore beconsidered.
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Vapor-Phase Transfers
Including Sublimation Pharmaceuticals containing components that
sublime easily may undergo changes in drugcontent owing to the sublimation of the drugsubstances or excipients.
In the case of nitroglycerin, which is a liquidwith a significant vapor pressure, sublingualtablets exhibited significant variations in drugcontent during storage owing to inter tablet
migration through the vapor phase This transfer was inhibited by adding water-
soluble nonvolatile fixing agents such aspolyethylene glycol.
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Kinetics of Solid-Phase
Transitions The Hancock.Sharp equation is often
used to describe the kinetics ofpolymorphic transitions:
In [In( 1 . ) = In B + m In t B is a constant
is the fraction of drug in the product stateover the fraction in the starting state.
By plotting the left-hand side of Eq.against the logarithm of time, a linearrelationship with a slope of m isobtained.
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Effect of Packaging on
Stability of Drug Products primary role of packaging, other than its estheticone, is to protect the dosage forms from moisture
and oxygen present in the atmosphere, light, andother types of exposure, especially if thesefactors affect the overall quality of the product on
long-term storage. Protection from light can be achieved using
primary packaging (packaging that is in directcontact with the dosage forms) and secondarypackaging made of light-resistant materials.
Incorporating oxygen adsorbents such as ironpowder in packaging units can reduce the effectof oxygen
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