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Solid state analysis and degradation profileDEPARTMENT OF QUALITY ASSURANCE 1
INTRODUCTION• The normal route of administration for most pharmaceutically active agents is through the use of solid dosage forms, and these units are ordinarily produced by the formulation and processing of powdered solids.• The priority of regulatory bodies has always focused on concerns of safety and efficacy, which led to emphasis on aspects of chemical purity.
• This situation has changed drastically over the past decade, with an ever-increasing degree of attention being given to the physical properties of the solids that compromise a dosage form.• solid-state reactions can affect the stability of a drug entity, so physical aspects of a formulation can not be ignored.
• sufficient physical information is necessary for formulator to overcome problems.• For a well-understood system, it is theoretically possible to design an automated or semi automated manufacturing scheme for which the processing variables are appropriately controlled and the possibility of batch failure is, hence, minimized.• It is presently recognized that to avoid problems during drug development, the physical characterization of bulk drugs, excipients, and blends of them should become part of the normal process.
• Study of polymorphs and solvatomorphs is very important.• The nature of the crystal structure adopted by a given compound upon crystallization exerts a profound effect on the solid-state properties of that system, and that these variations can translate into significant differences in properties is of pharmaceutical importance.• It is now accepted that an evaluation of the polymorphism available to a drug substance must be thoroughly investigated early during the stages of development.
• The results of these studies must be included in the chemistry, manufacturing, and control section of a new drug application, and such information is required to demonstrate control over the manufacturing process.• Therefore a systematic approach to the physical characterization of pharmaceutical solids has been outlined and serves as a useful device for the classification of the many methods of physical characterization.
• Based on this system, physical properties are classified as being associated with• The molecular level (those associated with individual molecules),• The particulate level (those pertaining to individual solid particles),• The bulk level (those associated with an assembly of particulate species).
• I. PROPERTIES ASSOCIATED WITH THE MOLECULAR LEVEL• A. Ultraviolet/Visible Diffuse Reflectance Spectroscopy• B. Vibrational Spectroscopy• C. Nuclear Magnetic Resonance Spectrometry• II. PROPERTIES ASSOCIATED WITH THE PARTICULATE LEVEL• A. Microscopy• B. X-Ray Diffraction• C. Thermal Methods of Analysis• III. PROPERTIES ASSOCIATED WITH THE BULK LEVEL• A. Particle Size Distribution• B. Micromeritics• C. Powder Characterization.
PROPERTIES ASSOCIATED WITH THE MOLECULAR LEVEL• A. Ultraviolet/Visible Diffuse Reflectance Spectroscopy• B. Vibrational Spectroscopy• C. Nuclear Magnetic Resonance Spectrometry
A. Ultraviolet/Visible Diffuse Reflectance Spectroscopy• Most solids are too opaque to permit the conventional use of ultraviolet/visible (UV/VIS) electronic spectroscopy.• As a result, such work must be performed using diffuse reflection techniques.• Ultraviolet/Visible Diffuse Reflectance Spectroscopy is applied to• -- study the reaction pathways of various solid-state reactions.• --The fields of colour measurement and colour matching, areas that can be of considerable importance when applied to the coloring agents used in formulations.
• It is very useful tool for the study of interactions among various formulation components, and the technique has been successfully used in the characterization of many solid-state reactions.• Investigations conducted under appropriately designed stress conditions have been useful in the study of drug-excipient interactions, drug degradation pathways, and alterations in bioavailability .
• EX: diffuse reflectance spectroscopy is used to study the adsorption of spiropyrans onto pharmaceutically relevant solids.• The particular adsorbents studied were interesting in that the spectral characteristics of the binary system depended strongly on the amount of material bound.• At low concentrations, the pyran sorbent exhibited its main absorption band around 550 nm.• As adsorption increased, the 550-nm band was still observed, but a much more intense absorption band at 470 nm became prominent.
• This secondary effect was attributed to the presence of pyran–pyran interactions, which became more important as the concentration of sorbent increased.
B. Vibrational Spectroscopy• Mid-infrared electromagnetic radiation is 400– 4000 cm−1 utilized for analysis based on fundamental vibrational modes of a chemical compound.• Fourier-transform infrared spectroscopy (FTIR) is now the method of choice.• Vibrational transitions also can be observed using Raman spectroscopy.• Overtones and combination bands of vibrational modes are observed in the near-infrared region of the spectrum (4000–13,350 cm−1).
• This all techniques are utilized for the physical characterization of pharmaceutical solids.• When the structural characteristics of a solid affects the pattern of vibrational motion for a given molecule, these alterations can be used as a means to study the solid-state chemistry of the system.• FTIR spectra often are used to evaluate : --the type of polymorphism that exists in a drug substance and --can be very useful to study the water contained within hydrate species.
• Solid-state IR absorption spectra often are obtained on powdered solids through the combined use of FTIR and diffuse reflectance detection, and interpreted through conventional group frequency compilations.• For example, glisentide has been obtained in a number of polymorphic and solvatomorphic forms, with the anhydrous forms I and II exhibiting large differences in infrared spectra.• The IR spectra of forms I and II are shown in Figure 1.
FIGURE 1 Infrared absorption spectra of glisentide: upper trace, form I; lower trace, form II.
• It can be noted that two bands assigned to the urea carbonyl group are found at 1635 and 1545 cm−1 in form I and at 1620 and 1545 cm−1 in form II. In addition, the shoulder that is present in both forms is more intense in the spectrum of form II.• The S O stretching band is observed at 1157 cm−1 in the spectrum of form I, but for form II it shifts to 1165 cm−1.• The aromatic carbonyl group at 1720 cm−1 is present in both spectra, but is broadened in the case of form II.
• Another technique of vibrational spectroscopy that is ideally suited for characterization of solids is Raman spectroscopy. In this methodology, the sample is irradiated with monochromatic laser radiation, and the inelastic scattering of the source energy is used to obtain a vibrational spectrum of the analyte.
• The Raman spectrum generally resembles the spectrum obtained using the FTIR method.• Differences in peak intensity are often observed. (Owing to the fundamentally different selection rules associated with the phenomenon)• In general, symmetric vibrations and non- polar groups yield the most intense Raman scattering bands. whereas antisymmetric vibrations and polar groups yield the most intense infrared absorption bands.
EX.• Raman spectroscopy was used to study the effect of pressure and temperature on the phase composition of fluoranil crystals.• Figure 2 shows the Raman spectra obtained at a series of increasing pressures, where the changes in band frequency indicate the existence of pressure-induced phase transitions.
FIGURE 2 Raman spectra obtained at 300 K for crystalline fluoranil at pressures of (a) 1 atm, (b) 0.5 GPa, (c) 1.4 GPa, and (d) 2.4 GPa.
• It was deduced from sharp discontinuities in the Raman spectra that a phase transition took place at a temperature of around 180 K if the pressure was 1 atm.• This transition shifted to 300 K if the pressure was increased to 0.8 GPa.
• Near-IR spectra consist of overtone transitions of fundamental vibrational modes and are not, therefore, generally useful for identity purposes without the use of multicomponent analysis.• But it is utilized in solid state analysis of the compounds that contain unique hydrogen atoms.• For example, studies of water in solids can be easily performed through systematic characterization of the characteristic OH band, usually observed around 5170 cm−1.• The determination of hydrate species in an anhydrous matrix can be performed easily using near-IR analysis.
• The near-IR technique has been used very successfully for moisture determination, whole tablet assay, and blending validation.• It is possible to use the overtone and combination bands of water to develop near- IR methods that have accuracy equivalent to that obtained using Karl–Fischer titration.
C. Nuclear Magnetic Resonance Spectrometry• The ultimate molecular level characterization of a pharmaceutical material is performed on the level of individual chemical environments of each atom in the compound, and this information is best obtained by NMR spectroscopy.• Advances in instrumentation and computer pulse sequences currently allow these studies to
• Solid-state NMR spectra is used to deduce nature of polymorphic variations, especially when polymorphism is conformational in nature. e.g. during development of Fosinopril sodium, a crystal structure was solved for most stable phase, but no such structure could be obtained for its metastable phase.
• NMR data suggest that additional conformational between the two polymorphs were associated with cis-trans isomerization along the peptide bond, which intern results in the presence of non equivalent molecules existing in the unit cell.
Why solid NMR spectrum is so different from liquid NMR?• There are 3 major factors: 1) dipolar broadening : The presence of a group of spins around a given spin may result in a number of interactions. The most important interaction between the spin and its surrounding spins is the dipolar interaction. It could be homonuclear or heteronuclear dipolar coupling. It is the dominant broadening factor in organic solids.
For the case of two spins, I and S , the approximate dipolar Hamiltonian can be written as: Hd = ½ ϒHϒCh2 (1-3cos2θ)(3IzSz-I×S) rHCin liquid, all possible values of θ exist due to reorientational motion. The average value of cos2 θ is 1/3, 1 and the dipolar coupling averages to zero. In a crystal powder or amorphous solid, all orientations occur, cos2 θ does not average to zero, there is a non
• -zero dipolar coupling, produce a broad line. This broadening may be of the order of 20 kHz. 2) Chemical Shift Anisotropy (CSA)• This broadening factor arises from asymmetry in the electron density surrounding a given nucleus. In liquids an average chemical shift is observed due to averaging over all orientations on a timescale short in comparison with the NMR measurement time.
• In solid, a complex line shape result from a sum of all possible chemical shifts.• The chemical shift anisotropy is again related to the term (3cos2θ-1). This term could be zero when the angle q is equal to 54044’. It is called magic angle.• In practical circumstances, high resolution solid state NMR spectra can be obtained using a combination of dipolar decoupling and magic angle spinning (MAS).
• The dipolar decoupling is similar to that observed in liquid NMR. When acquiring a 13C spectrum, proton decoupling is needed to decouple the proton attached to the carbon, since all other protons dipolar coupling are averaged by molecule self orientation.• In the solid ,high power decoupling is necessary because of abundance of NMR active nuclei nearby, and could not average the interaction to zero.
• This is one of the reasons to use MgO to dilute the organic solids sample to avoid homonuclear dipolar coupling. The effect of , MAS is to remove chemical shift anisotropy and dipolar coupling . However , in order to suppress dipolar couplings, the spinning speed should fast than the strength of coupling in Hz.
3) Spin-spin Relaxation and Spin Lattice Relaxation• The solids ,spin – spin relaxation time T2 is very short due to restricted motion. Under ideal conditions, the residual line width following decoupling and MAS will be determined by the magnitude of T2. the inherent line width is therefore much broad than that found in liquid state NMR, in tens of Hz is normal .
• In solid, spin lattice relaxation is very inefficient and T1 is very long, in tens of seconds, due to the restricted motion. A long pulse delay is required to re-establish thermal equilibrium. This could be over come by using cross polarization technique.• To observe rare spins 13Cin solids, there are no significant homonuclear couplings since they are far away from each other in the sample .on the other hand, the hetronuclear coupling between the rare spins(13C) and abundant spins(1H) are dominant.
• By using abundant spins to enhance the rare spin signals under appropriate condition is known as polarization transfer or cross-polarization.• In liquids, the polarization transfer was originally achieved by experiment INEPT. In solids , the polarization transfer could be achieved by spin lock under Hartmann- Hahn condition.
Properties Associated With ParticulateLevel:-• Particulate properties are defined as those material characteristics that effectively can be determined by the analysis of a relatively small ensemble of particles.I. Microscopyi. X-Ray diffractionii. Thermal mode of analysis
i. Microscopy :-Estimation of the particle size distribution in a powdered sample is obtained by microscopy method . The relative crystallinity of the material readily determined by this method .The micromeritic and bulk powder property of the material is highly influenced by the evaluation of the morphology of pharmaceutical solids.There are mainly two types of microscopy ; 1) Optical microscopy 2) Electron microscopy
Magnificent limit for Optical Microscopy for routine work is 600x,whereas electron microscopy can be performed at extraordinarily high magnification levels up to 90,000X on most units and the images contain three-dimensional information.
B)X-Ray Diffraction• The fundamental structural information on crystalline substances obtained by the technique of X-ray diffraction.• Bragg explained the diffraction of x-rays by crystals using a model where the atoms of a crystal are regularly arranged in space and where they can be regarded as lying in parallel sheets separated by a definite and defined distance.
• Application1) Determination of crystal structures2) Evaluation of polymorphism3) Solvate Structures4) Evaluation of degrees of crystallinity
(c) Thermal Methods of Analysis• This analytical method is used to characterize compound purity, polymorphism, salvation, degradation and excipient compatibility• By the thermal analytical method endothermic processes (melting, boiling, sublimation, vaporization, desolvation, solid-solid phase transitions and chemical degradation) as well as exothermic
• Processes (crystallization and oxidative decomposition) can be evaluated.• These are the techniques used to determine a property of the analyte as a function of an externally applied temperature. The property of analyte is evaluated on a continuous basis as a function of temperature.• The major advantage of this method is it is extremely useful during the conduct of preformulation studies, because carefully
• planned studies can be used to indicate the existence of possible drug-excipient interactions in a prototype formulation.
Differential Thermal Analysis(DTA)• This technique of thermal analysis is having an excellent qualitative advantage that is useful to deduce the temperature ranges associated with a variety of thermal events, as well as to assign the endothermic or exothermic nature of these reactions.• DTA represents an improvement to the melting point determination in that the
• Different temperature between the sample and a reference is monitored as a function of temperature.• However, differences in temperature between the sample and reference are manifested when changes occur that require a finite heat of reaction.• When the heat capacities of the two that is sample and reference roughly equivalent the temperature of the sample and the reference will be same due to the no theremal transitions take place
• If for the transition is positive (endothermic reaction) the temperature of the sample will lag behind that of the reference (because more heat will be absorbed by the sample than by the reference) and this event will be recorded in the thermogram as a negative-going peak.• If the H is negative (exothermic reaction) , the temperature of the sample will exceed that of the reference (because the sample itself will be a source of additional heat ) and the event will be recorded in thermogram as a positive going peak.
Differential scanning Calorimetry (DSC)• An improvement to DTA analysis is Differential scanning Calorimeter (DSC) and has become one of the most widely used methods of thermal analysis.• DSC method involves the measurement of the heat flow required to maintain the equality in temperature between the sample and the reference when they kept at same temperature.
• By placing separate heating elements in the sample and the reference cell, the equality can be achieved. The rate of heating by these elements is controlled and measured.• This method of measurement is termed power-compensation DSC, and it yields positive-going peaks for endothermic transitions and negative going peaks for exothermic transitions.
Lactos monohydrate (Fig:b)• The thermal transitions can be seen in the DSC curves. The curve for anhydrous lactose (fig. a) shows an endothermic melting peak at about 235 C• The lactose monohydrate (fig. b) dehydrates around 150 C ; the resulting anthydrous lactose melts at about 220 C• The small exothermic peak at 180 C can be attributed to the recystallisation of some of the anhydrous lactose into mixed crystal the thermal effects after the melting peak of lactose are the result of melting of the mixed crystal and of decomposition of the liquefied lactose.
Thermogravimetry (TG)• The thermally induced weight loss of a material is measured as a function of the applied temperature” is the main principle behind the thermogravimety (TG) of thermoanalytical technique.• The quantitative determination of the total volatile contents of a solid is the major use of TG analysis. The magnitude of each step can be separately evaluated, when a solid decompose by means of several discrete, sequential reactions.
• It is most commonly used to study desolvation Processes and compound decomposition because this method is restricted to studies that involve either a mass gain or loss (usually loss).• The stability of similar compounds can be compare by TG analysis of compound decomposition. The higher the decomposition temperature of given compound, the more negative is the G vaiue and therefore the greater is the stability.
For E.g Degradation pattern of CuSO4. 5H2O• CuSO4. 5H2O -- CuSO4. H2O (90 to150 C)• CuSO4. H2O --- CuSO4 (200 to 274 C)• CuSO4 ------CuS +SO2 ½ O2 (700 to 900 C)• 2CuO -- Cu2O + ½ O2 (1000 to 1100 C)
PROPERTIES ASSOCIATE WITH BULK LEVEL• Bulk properties are those characteristics of a solid that can be measured only for large ensemble particles.• In latter stages of drug development the physical characteristic compatibility of drug with other formulation ingredients is in important.• Excipients show physical effects like enhancing powder compaction promoting dissolution, modifying drug release rate and improve powder flowabillty
• This evaluation requires program for physical characterization of excipients especially w.r.t properties related to their use and functionaliy.
Particle size Distribution• Particle size distribution of API and excipients exerts profound effect on mixing and possible segregation and hence affect bioavailability and powder flowability.• In absence of electrostatic effects, it is easy to produce homogenously mixed powders if the individual components to be mixed are of equivalent particle size.
• All pharmaceutical dosage forms must be uniform and good content uniformity is possible only when particle size of API is carefully controlled.• Variety of methods are available for this determination• Optical microscopy (usually combined with image analysis )• Sieve analysis• Laser light scattering of suspended particles• Electrical zone sensing
• When proper sampling techniques are use, most absolute method used is Microscopy which becomes most efficient when combined with some form of image analysis• In automated method, microscope parameters are adjusted to optimize contrast between background and particles to be sized video image of powder is transmitted to a computer system which counts the number of pixels that make up a particle.
• The size of each pixel is easily converted to um and data are analyzed as desired- Average particle size, Full weight distribution or Shape information, etc.
Advantages of optical Microscopy :-• Provides direct and absolute information on the particles under study.• Sieve analysis is simplest and widely used method.• Here the particles are allowed to distribute among a series of sieves (typically wire mesh) and the amount of material retained on each sieve is determined.
• FINES– Smaller particles that passes through sieve• COARSE particles– Larger particles that remains on sieve• MEDIUM fractions – when multiple sieves are used the intermediate sized particles that passes through one or more sieve but retained on subsequent sieve.• Facilitation method like vibration ultrasound or air suspension are used to assist the passage of particles through various
• A proper size detemination required use of 5-6 sieves whose sizes are selected to obtain approx. equal amount of powder on each sieves and past the smallest sieve.• % material retained on each sieve. Cumulative% of sample retained and % sample passing each sieve are obtained.• Electrical zone sensing (is based on the coulter principle ) use measurement of electrical pulses caused by passage of particles through a sensing zone to get size information.
Micromeritics :-• For powders, micromeritics is related to the nature of the surfaces that make up the solid.• Of all the properties that could be measuredSurface areaPorosity andDensity are most revelant pharmaceutical parameters.
• SURFACE AREA – Provides information on the available void spaces on surface of a powdered solid and Dissolution rate is also partially determined.• Most reproducible measurements of the surface area of solids are obtained by adsorbing a monolayer of inert gas onto the solid surface at reduced temperature and subsequently desorbing this gas at room temperature. The sorption isotherms are them interpreted using equations of BET method.
• Unit- square meters of surface per gram of material• POROSITY – mercury intrusion porosimetry is the most widely used method to detemine pore size distribution of a porous Materials and void size of tablets and compacts. This method is based on capillary rise phenomena where excess pressure is required to force a nonwetting liquid into a narrow volume.
• Mercury with contact angle of approx. 140 with glass is commonly used as an intrusion fluid it is forced into the pores of a sample using as an intrusion fluid. It is forced into the pores of a sample using an externally applied pressure where the smallest pores require highest pressure to effect filling.• DENSITY- is ratio of mass to volume 3 types of density which differ in their determination of volume occupied by the powder are normally differentiated.
• Bulk density is obtained by measuring the volume of known mass of powder sample (that has been passed through a mesh screen ) into a suitable volume measuring apparatus like graduated cylinder. The bulk density is then obtained by dividing the mass of solid by the unsettled apparent volume.• Tapped density is obtained by measuring the volume of solid after subjecting the system to a number of controlled shocks. Into a smaller volume. So tapped density is always higher than bulk density.
• True density is an intrinsic property of the analyte and is determined by composition of the unit cell. It is average mass per unit volume, exclusive of all voids that are not a fundamental part of the molecular packing arrangement.• It is measured by Helium pycnometry, where the volume occupied by a know mass of powder is determined by measuring the volume of gas disolaced by the powder.
Powder Characterization• Flowability of powder is important parameter for formulators because the materials need to be moved from place to place.• E.g. For tablets compressed at high speed the efficiency of machine is suitable only it powder feed delievered at high rate.• Many pharmaceutical compounds with cohesive nature have undersirable flow properties.
• One of the alms of granulation is to reduce this cohesiveness to produce uniform blend with more suitable physical properties.• Powder flowability is evaluated using• Angle of repose (angle formed when a cone of powder is poured onto a flat surface)• Angle of spatula ( angle formed when material is raised on a flat surface out of a bulk pile)
• Compressibility (obtained from measurement of the bulk and tapped densities)• Cohesion (attractive forces that exist on particle surfaces )
IMPURITIES AND DEGRADATION PROFILE• What is Impurities ??? – Impurities in pharmaceuticals are the unwanted chemicals that remain with API or develop during formulation or upon aging. – The presence of these unwanted chemicals even in small amounts may influence the efficiency and safety of the products. 73
Source of Impurities in Formulation Impurities associated with Impurities created during formulation & API aging or related to formulation forms Organic Inorganic Residual Process Environmental Dosage Form FunctionalImpurities Impuritie Solvents Related Related factor related Group s related 74
Impurities Associated with API Organic Impurities (Process / Degradation Product) Starting By products Reagents, Degradation Material Ligands, Catalyst Product e.g.e.g. 4- Diacetylated Mandelic acid in e.g. Hydroxyaminophenol Paracetamol as Esomeprazole acid inin by product in Mag. Simvastatin,Paracetamol, manufacturing Impurity D inLoratadine in of Paracetamol AmlodipineDesloratadine Besylate 75
DEGRADATION• Solid state drug degradation occurs in a solution phase (in solvent layers associated with the solid phase ) source of solvent for such decomposition reaction may be :-• A) A melt from the drug it self or an ingredient in the formulation with low melting point• B) Residual moisture or solvent from wet granulation.
• C) Moisture adsorbed onto excipients such as starch, lactose, or microcrystalline cellulose.• D) Adsorbed atmospheric moisture or• E) Solvate or hydrate that losses its “bound” Solvent with time or temperature fluctuation.
Chemical decomposition of drugs insolid state can be divided into 4categories :-(1) solvolysis /Hydrolysis :-• It is most important reaction for solid state drug degrade on occuring mainly in compounds containing acy group involving decomposition of drug by reaction with solvent like Hydrolysis (with water as solvent) or other like decarboxylation, etc.
• Solvent acts as nucleophile attacking the electropositive center in drug molecules. E.g. NSAIDs, Barbiturates Vitamins, etc.
Protection against Hydrolysis• Hydrolysis occurs in presence of moisture H+ or OH so protection steps from this reaction mainly involves their elimination from the drug system like-• (a) Buffer :- it stabilizes the drug. Ph of solution is adjusted to give maximum drug stability and therapeutic activity.• (b) Complexation :- Hydrolysis of Benzocaine in aq solution is inhibited by addition of caffeine which forms a complex with it
• (c ) suppression of solubility :- as drug solubility decreases. The conc of drug in solution phase also decreases so rate of hydrolysis is reduced.• (d) Removal of water :- as water is responsible for hydrolysis its contacts with the drug is avoided in the preparation by• Storing drug in dry form E.g. streptomycin dry powder injection.• Using water immiscible vehicle for drug dispersion E.g. Aspirin in silicone fluid.
Oxidation• It involves interaction of a chemical with oxygen mostly in a solvent although there are examples where oxygen may be able to oxidize drug in absence of a solvent.• Oxidation means removal of electrons, electropositive atom or radical or addition of oxygen or removal of hydrogen• 2 main types are :-
• Proceed slowly under influence of atmospherice oxygen• Reversible loss of electrons without addition of Oxygen E.g. Adrenaline Riboflavin• In Pharmaceutical dosage forms, oxidation is usually AUTOOXIDATION (mediated by reaction with atmospheric oxygen under ambient condition ) E.g. Autooxidation of unsaturated fatty acids in fats and oils.
• E.g. Promethazine, Vitamin A Riboflavin Morphine, etc.• System can be protected against oxidation by following ways :-• (a) Antioxidants : - they or prevent the oxidation process. E.g. Tocopehrol, Butylated Hydroxyl Anisole (BHA) , Butylated Hydroxyl Toluene (BHT), propyl gallate, etc,• (b) Adjustment of Ph :- Potential (E) is influenced by PH of system . Decrease in Ph caused rise in E and hence increases resistance to oxidation.
• (c ) Micellar Solubilization :- Surfactans such as polysorbate enhances the rate of oxidation ascorbic acid at low conc but protects above its critical micelle conc (CMC) by entrapping the drug in spherical micelle.
Photolysis• Photolysis of drugs like phenothiazine and vitamin A need Presence of solvent but sometimes such solvent-dependant reaction may not be needed.• Light may cause substantial degradation of drug molecule by absorbing energy of particular wavelenght.• Photochemical reaction – Molecules absorbing light takes part in photolysis and photosensitization –absorbing molecules don’t participate in photolysis.
• Photons of shorter wavelength have more energy so uv visible light can cause phctolysis.• E.g. Photodegradation of sodium Nitroprusside in aq solution• Photo toxicity caused by drug is common Problem the Primary reaction for initiating this toxicity is generation of singlent-state excited oxygen.• Prevention-store in dark or enclose it in an opaque wrapper or in light resistance containers which donot transmit more than 15 % of incident radiation between 290-
Pyrolysis• It is thermally induced bond rupture occuring in absence of solvent. It is normally not an important mechanism except when the drug is exposed in processing to a very high temp.• E.g. P-aminosalicylic acid degradation at 70-80 c range in the absence of molsture show a significant pyrolysis.
REFERENCES• 1) Ahuj Satinder, scypinki stephen. Handbook of modem Pharmaceutical analysis 3rd ed. Academic press• 2) Zornoza A, de No. C., Goni M.M. Martinez Oharriz M.C., and Velaz I lnt J. pharm. 186. 199. 1999.• 3) http:/www.emory.edu/NMR/Hall/solid/index .htm• 4) http:/www.bionmr- c1.unl.edu/921/Lectures/chapter11-solid-