SEMINAR ON DRUG EXCIPIENT COMPATIBILTY STUDY (As a part of preformulation study)

INTRODUCTION
INCOMPATIBILITY -Definition -3 Types OBJECTIVE OF THE STUDY -Why to screen excipients? 1.need to minimize no of model formulations 2.provide rational basis for selecting excipients 3.Formulation stability studies are time consuming. -Goal of the study( Identify the excipients that) 1.are compatible with API 2.do not have impact on the stability of API -Importance 1.Stabity of formulation can be maximised. 2.Helps to avoid surprise problems. 3.Essential for IND submission. 4.Bridges drug discovery and drug development

COMPATIBILITY TESTS
2 Aspects of compatibility tests are: 1. Identification of compatible excipients for a formulation. 2. Identification of stable storage conditions 2 Types: 1. Solid state reactions: - much slower and difficult to interpret. 2. Liquid state reactions: - easier to detect - Acc. to Stability Guidelines by FDA following conditions should be evaluated for solutions or suspensions 1. Acidic or alkaline pH. 2. Presence of added substances 3. High oxygen and nitrogen atmospheres. 4. Effect of stress testing conditions.

STEPS IN COMPATIBILITY STUDY

There are THREE steps to consider. 1. Sample preparation 2. Storage 3. Method of analysis

SAMPLE PREPARATION
FOR SOLID STATE REACTIONS: SampleA: -mixture of drug and excipient SampleB: -SampleA+ 5% moisture SampleC: -Drug itself without excipients o All the samples of drug-excipient blends are kept for 1-3 weeks at specified storage conditions. o Then sample is physically observed . o It is then assayed by TLC or HPLC or DSC. o Whenever feasible, the degradation product are identified by MASS SPECTROSCOPY, NMR or other relevant analytical techniques. o To determine Solid state stability profile of a new compound. o To test the Surface Oxidation..

SAMPLE PREPARATION
FOR LIQUID STATE REACTIONS: o Place the drug in the solution of additives. o Both flint and amber vials are used. o This will provide information about -Susceptibility to oxidation. -Susceptibility to light exposure. -Susceptibility to heavy metals. o In case of oral liquids, compatibility with ethanol, glycerin ,sucrose, preservatives and buffers are usually carried out.

STORAGE CONDITION
The storage conditions used to examine compatibility can very widely in term of temp. & humidity, but a temp. of 50c for storage of compatibility sample is considered appropriate. Some compounds may require high temp. to make reaction proceed at a rate that can be measured over a convenient time period.

ANALYTICAL TECHNIQUES USED TO DETECT DRUS-EXCIPIENT COMPATIBILITY

1. Thermal methods of analysis DSC- Differential Scanning Calorimetry DTA- Differential Thermal Analysis Accelerated Stability Study FT-IR Spectroscopy DRS-Diffuse Reflectance Spectroscopy Chromatography SIC-Self Interactive Chromatography TLC-Thin Layer Chromatography HPLC-High Pressure Liquid Chromatography Miscellaneous Radiolabelled Techniques Vapour Pressure Osmometry Flourescence Spectroscopy

2. 3. 4. 5.

6.

DSC- DIFFERENTIAL SCANNING CALORIMETRY

o DSC is widely used to investigate and predict any physicochemical interaction between drug and excipients involving thermal changes.. o METHOD -The preformulation screening of drug-excipient interaction requires (1 : 1)Drug:excipient ratio, to maximize the likehood of observing an interaction. -Mixture should be examined under N2 to eliminate oxidative and pyrrolytic effects at heating rate ( 2, 5 or 100 c / min) on DSC apparatus.

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EXAMPLE: DSC IN OFLOXACIN TABLETS

Trace 1 of figure 1-4 shows peak at 278.330C. (melting endothermic peak of Ofloxacin). Trace 3 (Physical mixture of Ofloxacin & Lactose) shows absence of peak at 278.330C and slight pre shift in Lactose peaks. DSC RESULT-- INCOMPATIBLE
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Trace 5 (Physical mixture of Ofloxacin & Starch) shows an early onset at 268.370C. But no other changes in thermogram. DSC RESULT-- COMPATIBLE
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Trace 7 (Physical mixture of Ofloxacin & PVP) shows no change in position of endothermic peak for PVP but there is increase in peak area and size & shape of peak for Ofloxacin is also decreased. DSC RESULT-- INCOMPATIBLE

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Trace 9 (Physical mixture of Ofloxacin & Talc) shows combine features of each component but there are evident changes in onset. DSC RESULT-- COMPATIBLE
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DSC STUDY IN ASCORBIC ACID FORMULATION

oExcipients: Sod. Crosscarmellose, MCC, Lactose oThermal stability was performed on ascorbic acid std. samples, binary mix. of ascorbic acid & excipients, under N2 & air atmospheres. oIR & X-Ray Diffractometry: No chemical interaction However thermal stability of pceutical formulations are different. oTemp. of beginning of thermal dregradation for Ascorbic acid is lowered of about 50C for MCC & 100C for Nacrosscarmellose & Lactose. oSuch facts must be considered for storage planning of tablets.
(Ref: C.A. vol:146, No:25, June18,2007,507180t) 16

LIMITATIONS OF DSC
o If thermal changes are very small, DSC cant be used. o DSC can not detect the incompatibilities which occur after long term storage. Eg. MCC / ASPIRIN o Not applicable if test material exhibits properties that make data interpretation difficult. o ADVANTAGES: -Fast -Reliable and very less sample required.

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DIFFERENTIAL THERMAL ANALYSIS(DTA)

Thermal Analysis is useful in the investigation of solidstate interactions. It is also useful in the detection of eutectics. Thermograms are generated for pure components and their physical mixtures with other components. In the absence of any interaction, the thermograms of mixtures show patterns corresponding to those of the individual components. In the event that interaction occurs, this is indicated in the thermogram of a mixture by the appearance of one or more new peaks or the disappearance of one or more peaks corresponding to those of the components.

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DTA( DRUG:ENALAPRIL MALEATE)

FORMULATION RESULT OF DTA
(interaction)

SHELF LIFE

INFERENCE

F1 (Avicel) F2 (Spray dried lactose)

F3 (Emcompress) F4 (A-tab)

+
+ +

3 month 1 yr and 3 month

8 month 9 month

Least suitable Ideal

Not recommended Not recommended
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(Ref:I.J.P.E.,Jan:2000,153)

ACCELARETED STABILITY STUDY

oDifferent formulations of the same drug are prepared. oSamples are kept at 40C / 75 % RH. oChemical stability is assessed by analyzing the drug content at regular interval. oAmt. of drug degraded is calculated. o% Drug decomposed VS time(month) is plotted.
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DIFFUSE REFLECTANCE SPECTROSCOPY

Principle: Penetration of a portion of incident radiation flux into the interior of the solid sample, return of some portion of radiation to the surface of sample following partial absorption and multiple scattering at boundary of individual sample particles. Detects the decomposed products, along with physical and chemical adsorption of excipients on to A.P.I. and vice versa. Example: Ethanol mediated interaction between dextroamphatamine sulphate and spray dried lactose in solidsolid mixture: Discoloration of powdered mixture was accelerated by 2 amine and by storage at elevated temp. Two new absorption maxima were observed at 340 nm & 295 nm resply. A + L = AL AHMF

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DIFFUSE REFLECTANCE SPECTROSCOPY

A shift in the diffuse reflectance spectrum of the drug due to the presence of the excipient indicates physical adsorption. whereas the appearance of a new peak indicates chemisorption or formation of a degradation product. DRS is more useful than HPLC assay to detect surface discoloration due to oxidation or reaction with excipients.

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SELF INTERACTIVE CHROMATOGRAPHY

SIC is useful for proteinous drug and excipients. METHOD: SIC is a modified type of affinity chromatography. Here,drug is made immobilized as the SP & soln. to be tested( excipient soln.) acts as MP. Measure Rt (Retention time) & compare with non retained marker.

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PRINCIPLE:For different mobile phases (i.e. different excipients) the injected drug have different interactions (may be repulsive or attractive) with the SP of drug leads to shift in retention time (Rt)

FIGURE-1

FIGURE-2

FIGURE-3

When interaction is repulsive,a sharper peak is obtained at a shorter retention time

When no net interaction between the immobilized drug,Rt=dead volume of column.

When attractive interactions,it will have longer retention time& wider peak
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TLC AND HPTLC

o TLC is generally used as confirmative test of compatibility after performing DSC. o S.P. consist of powder (Silica, Alumina, Polyamide, Cellulose & Ion exchange resin) adhered onto glass, plastic or metal plate. o Solution of Drug, Excipient & Drug: Excipient mixture are prepared & spotted on the same baseline at the end of plate. o The plate is then placed upright in a closed chamber containing the solvent which constitutes the M.P.

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TLC AND HPTLC

Any change in the chromatograph such as the appearance of a new spot or a change in the Rf values of the components is indicative of an interaction. The technique may be quantitated if deemed necessary. If significant interaction is noticed at elevated temperatures, corroborative evidence must be obtained by examining mixtures stored at lower temperatures for longer durations. Among the advantages of thin-layer chromatography in this application are: Evidence of degradation is unequivocal. The spots corresponding to degradation products can be eluted for possible identification.

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HPLC AND FLUORESCENT MEASUREMENT

HPLC (high pressure liquid chromatography) Characteristics: -The APIs and model compounds of diversified chemical structure was studied. -Elution rate: 7.5 ml/hr at ambient temp. -Allows the detection and quantification of impurities, which span a wide range of polarities, including nonpolar compounds. FLUORESCENT MEASUREMENT: -This technique is restricted to those compounds, which can generate florescence. As the no. of such compounds are restricted, this method is used in Analysis and not in preformulation
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 VAPOR PRESSURE OSMOMETRY & EQUILIBRIUM DIALYSIS

Principle: samples of solutions and pure solvent are introduced into a temperature-controlled enclosure, which is saturated with solvent vapor.Since the vapor pressure of solution is lower than that of solvent, solvent vapor condenses on solution sample causing its temperature to rise. The temperature rise is predicted by Clausis Clapcyron equation. Characteristics: Either liquid or solid sample and must be soluble in organic solvent or in water Sample must not undego association in solution. Sample size is approx. 3 gms for multiple analysis. Measures a no. of avg. mole. Wt. of about 10,000 Daltons. This method measures interactions, & records the interaction caused by variation of particle no.

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 RADIO LABELLED TECHNIQUES:

It is important when the API is having radio activity. Method is carried out by using either 3H or 13C. Highly sensitive method but the cost of carrying out the method & the availability of well established other techniques & methods, this method is generally not preferred.

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INCOMPATIBLE IMPURITIES
o Chemical impurity profiles -Very important in influencing the long term chemical stability. Eg:(1) Evaluation of Hydroperoxides ( HPO) in common pharmaceutical excipients. POVIDONE Contains substantial conc. PEG 400 of HPOs with significant HPC batch to batch or mfger POLYSORBATE 80 to mfger variations. o While MCC, Lactose, High M.wt PEG, Polyxamer contains less amt. of HPOs. o 5% PVP responsible for N-oxide formation of Raloxifen HCl, due to high HPO content.
(Ref: J.Ph.Sci,vol:97,Jan:2007,106)

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(2) DCP Sometimes, IRON may be present in DCP as impurities. It is incompatible with MECLIZINE HCl . (Fe NMT 0.04%) (3)Gelatin is also containing IRON as impurities, Dark spots may occur in the shell due to the migration of water soluble iron sensitive ingredients from fill material into the shell.

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P- Glycoprotin inhibitor excipients

o p-Glycoprotein is membrane associated transport protein. It is an efflux pump lies in tissue membranes. o Some excipients have p-Glycoprotein efflux-pump inhibiting properties.

o EXAMPLES:-

1.PEG-32 lauric glycerides. 2.Polysorbate-80 3.PEG-50 Stearate 4.Polysorbate-20 5.Polysorbate-85 6.PEG-40 hydrogenated castor oil 7.PEG-35 castor oil
(Ref: J.Ph.Sci.,vol:93,Nov:2004,2755)

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Known Incompatibilities
Functional group Primary amine Ester, Lactone Aldehyde Carboxyl Alcohol Sulfhydryl Phenol Gelatin- Capsule Shell Incompatibility Mono & Di-saccharides Type of reaction Amine-Aldehyde & Amine-Acetal Ester base hydrolysis, opening, Ring

Basic component

Amine, Carbohydrate Base Oxygen Oxygen Metal Cationic Surfactant

Aldehyde-Amine, Schiff base Or Glycosylamine formation Salt formation Oxidation to Aldehyde & Ketones Dimerization Complexation Denaturation
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Excipient
Parabens

Incompatibility
Non ionic surfactants (Polysorbate 80)

Type of reaction
Micellization (Reduced antimicrobial activity)

Plastic Containers
Phenylmercuric Nitrate Anionic Emulsifying agents, Suspending Agents, Talc, Nametabisulfite, Na-thiosulfate Halides PEG Penicillin & Bacitracin Phenol, Tannic acid & Salicylic acid Sulphonamide & Dithranol Film coating

Absorption of Parabens
Anti-microbial activity Reduced Incompatible (forms less soluble halogen compds) Anti-bacterial activity reduced Softening & Liquifaction Discoloration Migration of PEG from tablet film coating, leading to interaction with core component
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DECS in solid dosage forms

Example 1:o Millard reaction:- is a non-enzymatic bimolecular browning reaction between reducing sugar and an amine.(Anhydrous lactose: no Millard reaction) o Mechanism:-

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Example2:-

Effect of Excipients on Hydrate formation in wet masses containing Theophylline

oDuring wet granulation Theophylline Shows Pseudopolymorphic changes that may alter its dissolution rate.In the presence of moisture Theophylline monohydrate is formed which has slow dissolution rate. oDiluents Used: 1.- Lactose monohydrate : Minimum water absorbing capacity. So not able to prevent but enhance Hydrate formation of Theophylline. 2.Silicified MCC : Highly water absorbing capacity.Able to inhibit the formation of Theophylline monohydrate at low moisture content.
(Ref- J.Ph.Sci,vol:92,Jan:2003,516) 36

SILICIFIED MCC as a multifunctional pharmaceutical excipient

Multifunctional excipient Characteristics offered by Prosolv are high compactibilty, high intrnsic flow, enhanced lubrication efficiency and improved blending properties. Provide tremendous advantages through out product life cycle. MCC is a dry binder- when comes in contact with water ,its compressibilty is decreased..but that is not the case with SMCC.
(Ref:CA,Vol:151,No:6, August10,2009 ,131557w)

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DRUG EXCIPIENT COMPATIBILTY STUDY IN AEROSOLS

o Example 1:- Interaction of propellent-11 with aqueous drug products.

o Propellent 11 is trichloromonofluoromethane.
o HCl corrodes the Al-container.
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Example2: Beclomethasone- Hydroflouroalkane interactions: BDP is a Steroidal drug used in Asthma

Manipulation of above interaction: BDP particles

coated with amphiphilic macromolecular excipient by Spray drying. Therefore, prevention of aggregation & production of physically stable suspension with excellent aerosolisation properties.
(Ref: J. Ph.Sci.,VOL:95,May:2006,1060)
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oAnhydrous ethanol is corrisive to Al containers.

-Hydrogen produced in the reaction increases the pressure of the container.So drugs containing polar solvents tend to be corrosive to bare Al. oFor containers which contain 2%Tin and 98% Lead
-Lead reacts with the fatty acids(for product cont.soaps) to form Lead salts which cause valve clogging.

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DRUG EXCIPIENT COMPATIBILTY IN PARENTERAL PRODUCTS

Anti-oxidants
Ascorbic acid: Incompatible with acid- unstable drugs Na bisulfite:+ Epinephrine Sulphonic acid dvt. -Incompatible in Opthalmic solution containing Phenyl mercuric acetate Edetate salts: Incompatible with Zn Insulin, Thiomerosal, Amphotericin & Hydralazine

Preservatives
Phenolic Preservatives -Lente- Insulin + Phenolic preservative sulphide Linkage in Insulin structure. Break-down of Bi-

-Protamine- Insulin + Phenolic preservative tetragonal oblong crystals which is responsible for prolong action of insulin.
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 Surface active agents

Cosolvants

Polysorbate 80: One must concern about the residual peroxide present in Polysorbate. PS 80 Polyoxyethylene sorbitan ester of Oleic acid ( Unsatd.F.A) PS 20 Polyoxyethylene sorbitan ester of lauric acid ( Satd.F.A) So PS 20 is less prone to oxidation than PS 80. Sorbitol Increase the degradation rate of Penicillin in Neutral and Aqueous solutions. Glycerol Increase the mobility of freeze-dried formulation leading to peptide deamidation.

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COSOLVENTS
Sr . N o. 1.
DRUG EXCIPIENT INTERACTION OBSERVED

Nicotinamide & dimethylisosorbide

Paclitaxel, Diazepam, Propaniddid and Alfaxalone

Propylene-glycol
Cremophor EL (polyoxyl 35 castor oil)

Hemolysis (in vivo effect)

Precipitation of Cremophor EL

2.

OILS AND LIPIDS

Sr. No. 1.

DRUG Lidocaine Calcium chloride, phenytion sodium, tetracycline hydrochloride

EXCIPIENT Unpurified sesame oil Soybean oil

INTERACTION Degradation of lodocaine Incompatible with All.

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2.

SURFACTANTS & CHELATING AGENTS

DRUG Proteins EXCIPIENT Tween 80 and other nonionic polyether surfactants Thiols such as cystiene, glutawthion e asnd thioglycerol Modified cyclodextrins, INTERACTION OBSERVED Surfactants undergo oxidation and the resultant alkyl hydroperoxides formed contribute to the degradation of protein. Most effective in stabilizing protein formulations containing peroxideforming surfactants.

Protein formulations

Dexamathasone, Estradiol, Iterleukin-2 & Proteins and Peptides

Solubilize and stabilize drugs without apparent compatibility problems.

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BUFFERS,ANTIMICROBIALS & ANTIOXIDENTS

DRUG
N-nitrosourea 5-flurouracil

EXCIPIENT
Tris buffer Tris buffer

INTERACTION
Form stable complex with N-nitrosourea and retard the degradation of this agent. Tris buffer will degrade 5-flurouracil, causing the formation of two degradation products that can cause serious cardiotoxicities Incompatible

Chlorpromazine Recombinant human interferon gamma Cisplatin

Meta-cresol Benzyl alcohol

Benzyl alcohol caused the aggregation of the protein Sodium metabisulfite inactivates cisplatin

Sodium metabisulfite

JPS 2002, Vol. 91, No. 9-12, page 2283-2296.

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REFERENCES
Pharmaceutical Dosage forms By Leon Lachman & Liberman Hand book of Pharmaceutical Excipients Remingtons Pharmaceutical Science,21st edition,2005. Modern Pharmaceutics by Banker & Rhodes,4th edition,2002. Theory and Practice of Industrial Pharmacy by Lachman & Lieberman. Int. J. Ph.Exci., Vol-1, Jan-2000, 153. Int. J. Ph.Exci., Nov-2002, 2283 Int. J. Ph.Exci.,jan-march,2003 J. Ph. Sci..,Vol-97, Jan-2007,106 J. Ph. Sci., Vol-95, May-2006, 976. J. Ph. Sci., Vol-95, May-2006, 1060. J. Ph. Sci., Vol-95, June-2006, 1342. J. Ph. Sci., Vol-93, Jan-2004,132 J. Ph. Sci., Vol-93, Nov-2004, 2755. J. Ph. Sci., Vol-92, May-2003, 516. JPS 2002, Vol. 91, No. 9-12, page 2283-2296 C.A. vol:146, No:25,June 18 :2007,507180t C.A. vol:147, No:4, July 23 :2007,79121 CA,Vol:151,No:6, August10,2009 ,131557w

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