Solid State Stabilityanis

8/10/2019 Solid State Stabilityanis

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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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Solid State Stabilityanis