Drug Excipient Compatibility Testing Protocols and ...

_____________________________________________________________________________________________________ *Corresponding author: E-mail: [email protected], [email protected];

Asian Journal of Chemical Sciences 6(3): 1-22, 2019; Article no.AJOCS.51941 ISSN: 2456-7795

Drug Excipient Compatibility Testing Protocols and Charaterization: A Review

Krishna R. Gupta1*, Anita R. Pounikar1 and Milind J. Umekar1

1Department of Pharmaceutical Chemistry, Smt. Kishoritai Bhoyar College of Pharmacy,

New Kamptee, Nagpur, India.

Authors’ contributions

This work was carried out in collaboration among all authors. Author KRG wrote the final draft of the manuscript. Author ARP wrote the first draft of the paper. Author MJU managed the literature

searches. All authors read and approved the final manuscript.

Article Information

DOI: 10.9734/AJOCS/2019/v6i319000 Editor(s):

(1) Dr. Fahmida Khan, National Institute of Technology, Raipur, Chhattisgarh, India. Reviewers:

(1) Debarshi Kar Mahapatra, Dadasaheb Balpande College of Pharmacy, India. (2) Buchi N. Nalluri, KVSR Siddhartha College of Pharmaceutical Sciences, India.

Complete Peer review History: http://www.sdiarticle4.com/review-history/51941

Received 28 July 2019 Accepted 04 October 2019

Published 22 October 2019

ABSTRACT

Drug molecule contains various reactive functional groups which are susceptible to react with another reactive functional groups which might be excipients, excipient or drugs impurities formed during manufacturing or storage. The objective of the current review article is to provide a comprehensive review of excipients-drug compatibility study, their degradation product characterization with different analytical methods and further impact of methodologies in pharmaceutical industry for potential stability assessment. The incompatibility of drug excipient was very common due to the reactive functional groups in drugs and excipients. These leads to formation of drug related impurities as well as excipient impurities reaction with active Pharmaceutical Ingredients. Sometimes these impurities found to be mutagenic and genotaxic to human beings. Identification of drug degradation in presence of excipient impurities requires extensive knowledge and adequate analytical characterization data. Systematic literature review and understanding about the drug-excipient chemistry in formulation process is important criteria to select compatible excipient and formulate ideal formulation. The analytical characterization data gives idea about degradation pathway. This paper discusses drug-excipient interactions, compatibility and characterization by different analytical methods with case studies and provides an overview of different excipients compatibility in formulation.

Review Article

Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article no.AJOCS.51941

2

Keywords: Different excipients; reactive functional groups; degradation products; characterization.

1. INTRODUCTION Different dosage forms like tablets, capsules, oral liquids, injectable products, implants, eye products, nasal products, inhalers, topical creams and gels, transdermal patches and suppositories etc, contains different types of excipients. To make it acceptable and compatible various pharmaceutical excipients are added in pharmaceutical dosage form for their direct therapeutic action, manufacturing process, to protect, support or enhance stability, for bioavailability or patient compliance. The common excipients used in tablets are listed in Table 1 [1].

Drug degradation catalyzed by excipients impurity reaction with reactive functional groups of organic active pharmaceutical ingredient. Functionality, compatibility between the drug and excipients are the most important criteria for the selection of pharmaceutical excipients and their concentrations in formulation. Because of an incompatibility between drug and excipient in the formulation affect the various pharmaceutical properties like changes in physical, chemical, microbiological or therapeutic properties of the dosage form. Various analytical methods incorporated mainly to estimate the potential incompatibility of the drug, degradation pathways, impurities and their concentration in

the final dosage form to prevent further incompatability. The common pharmaceutical excipients and their potentially reactive impurities are listed in Table 2. Many formulations undergo reactions such as hydrolysis, isomerization, dehydration, oxidation, photodegradation, elimination, cyclization and specific interactions with formulation excipients and their impurities observed in pharmaceuticals. Interaction and incompatabilities of the excipients with functional groups and different types of reaction are listed in Table 3. The environmental factors such as temperature, pH and moisture in solids, relative humidity of the environment, presence of catalysts, light, oxygen etc, and acts like a catalyst to initiation of drug excipients reaction. Moisture increases the micro-environmental pH in the dosage form leads to acid–base catalysis reaction of drug excipients and source of impurities results in drug degradation [2].

1.1 Isothermal Stress Testing In isothermal stress testing, drug excipient blends in the presence of moisture (20%) exposed to constant temperature for specific period of time. The total no. of drug excipient blends were planned as per statistical design.

Table 1. Common excipients used in tablets

Sr. No. Excipient Function Examples

1 Diluent Provide bulk and enable accurate dosing of potent

ingredients

Sugar compounds e.g. lactose, dextrin, glucose, sucrose, sorbitol

Inorganic compounds e.g. silicates, calcium and magnesium salts, sodium or potassium chloride

2 Binders,

compression aids,

granulating agents

Bind the tablet ingredients together giving form and

mechanical strength

Mainly natural or synthetic polymers e.g. starches, sugars, sugar alcohols and cellulose derivatives

3 Disintegrants Aid dispersion of the tablet in the gastrointestinal tract, releasing the active ingredient and increasing the surface area for dissolution

Compounds which swell or dissolve in water e.g. starch, cellulose derivatives and alginates, crospovidone

4 Glidants Improve the flow of powders during tablet manufacturing by reducing friction and

Colloidal anhydrous silicon and other silica Compounds


3

Sr. No. Excipient Function Examples adhesion between particles. Also used as anti-caking agents.

5 Lubricants Similar action to glidants, however, they may slow

Disintegration and dissolution. The properties of glidants and lubricants differ, although some compounds, such as starch and talc, have both actions

Stearic acid and its salts (e.g. magnesium stearate)

6 Tablet coatings

and films

Protect tablet from the environment (air, light and

moisture), increase the mechanical strength, mask

taste and smell, aid swallowing, assist in product

Identification. Can be used to modify release of the active ingredient. May contain flavours and colourings

Sugar (sucrose) has now been replaced by film coating using natural or synthetic polymers. Polymers that are insoluble in acid, e.g. cellulose

acetate phthalate, are used for enteric coatings to delay release of the active ingredient

7 Colouring agents

Improve acceptability to patients, aid identification

and prevent counterfeiting. Increase stability of lightsensitive drugs.

Mainly synthetic dyes and natural colours. Compounds that are themselves natural pigments of food may also be used

1st phase (Selection of diluent and lubricant): The compatibility of drug with diluents and lubricants is tested by storing them in various conditions for a particular time period. 2nd phase (Selection of disintegrant and binder): Using diluents- lubricant mixture selected in the first phase, the compatibilityof other excipient such as binder and disintegrant were tested in 2

nd phase [3].

1.2 Protocol for Compatibility Testing Compatibility studies designed to identify key drug–excipient incompatibilities, causes and effects. Compatibility studies started with the evaluation of existing information and chemistry of the new molecular entities to identify “soft spots” in the molecule. Selected excipients evaluated for the presence of reactive or unstable functional groups, pKa value and known reactivities of similar compounds. General literature, several computational programs or softwares like e.g., CAMEO R , SPARTAN R , EPWIN R and Pharm D 3R etc can be used. To detect the presence and extent of known reactivities, the compatibilitystudy design

modulated by physico-chemical characterization and forced degradation of the drug molecules. Design of compatibility studies might involve:-

Use of mixtures of drug with one or more excipients and water is added to accelerating drug – excipient interactions. Also hydrogen peroxide can be added to induce oxidative stress.

Incubation at various elevated temperatures, and analyzed for physical and chemical changes in the drug at predetermined time intervals.

Analysis of binary mixtures of drug and excipients by thermal methods such as differential scanning calorimetry (DSC) and isothermal microcalorimetry (IMC), for rapid assessment of potential incompatibilities.

1.3 Experimental Design of Compatibility Study

It involves

1. Two - or Multi-component Systems:- The binary mixtures include drug and common pharmaceutical excipients such


4

as diluents and in ternary mixtures of drug, a diluent and excipients used in lower proportions such as disintegrants and lubricants, that are incubated at accelerated conditions like pH, Temperature, Humidity, Oxidative conditions or Radiations etc. The variance is calculated by F-ratio analysis and it applied to test whether the normally distributed populations are equal and by the calculation of p-value.

2. The n-1 Design and Mini-formulations: - The Plackett–Burman design may applied to Mini-formulations which involved

ingredients such as colours and flavors, from solutions and suspensions are prepared with the exclusion of non-critical, quantitatively minor and/or easily interchangeable ingredients. Minimum number of experimental runs, which can be easily capable of finding the excipients that cause major incompatibilities.

3. n-1 design:- n - excipients analyzed by n+1 experimental runs design. In this study, eight experiments included over the minimum required to study the effect of “pseudo-variables,” to account for random experimental variation.

Fig. 1. Typical modalities of compatibility testing

Fig. 2. Typical modalities of compatibility study execution. Various stages of the compatibility testing

Background information

and literature review

Study design

Sample preparation

Incubation at

stressed conditions

Analyses and

data interpretation

Binary, ternary mixtures or mini formulations or n-1

design

Physical mixtures Compaction Effect of water • Incubation in RH chambers • Addition in sealed container

Physical (color) changes Thermal changes by DSC Drug degradation by HPLC Form change by PXRD

Temperature Humidity UV for photostability Oxidizing agents


5

1.4 Impurities Present in the Excipients Various pharmaceutical excipients used in formulation for different purposes, but due to

their own degradation or incompatibilities with drugs. Table 2 shows various excipients, reactive impurities and known incompatability.

Table 2. The common pharmaceutical excipients and their potentially reactive impurities

Sr. No.

Excipient Potentially reactive impurities

Examples of known incompatibilities

1 Lactose Glucose, furfuraldehyde, formic acid, acetic acid and potentially other aldehydes.

Maillard reactions, Claissen – Schmidt condensation reaction of its impurity, 5 hydroxylmethyl-2 furfuraldehyde and catalysis of hydrolysis.

2 Microcrystalline Cellulose

Glucose, formaldehyde, nitrates and nitrites

Water sorption resulting in increased hydrolysis, Maillard reaction with residual glucose, adsorption of basic drugs, and non-specific incompatibilities due to hydrogen bonding capability

3 Povidone and Crospovidone

Povidone and crospovidone contain significant levels of peroxides. Povidone may also contain formic acid and formaldehyde

Oxidation attributable to peroxides, nucleophilic addition to amino acids and peptides, and hydrolysis of sensitive drugs due to moisture

4 Hydroxypropyl cellulose (HPC)

HPC may contain significant levels of peroxides.

Oxidation of sensitive drugs due to residual peroxides

5 Croscarmellose sodium

Monochloroacetate, nitriles, and nitrates. Monochloroacetate can react with nucleophiles

Weakly basic drugs can compete with the sodium counterion, thus getting adsorbed on the surface of the disintegrant particles. Drug salt form conversion has also been reported.

6 Sodium starch glycolate

Monochloroacetate, nitriles, and nitrates are potentially reactive impurities.

Adsorption of weakly basic drugs and their salts due to electrostatic interactions.In addition, the residual monochloroacetate may undergo S N 2 nucleophilic reactions.

7 Starch Starch may contain formaldehyde, nitrites and nitrates

Terminal aldehydes in starch have been known to react with the hydrazine moiety of hydralazine HCl.Starch may also be involved in moisture-mediated reactions, may adsorb drugs, and may react with formaldehyde resulting in reduced functionality as a disintegrant.

8 Colloidal silicon dioxide

May contain heavy metal impurities

May act as a Lewis acid under anhydrous conditions and may adsorb drugs

9 Magnesium stearate

Magnesium oxide is a known reactive impur

Magnesium stearate can form hydrates with water, and exists in four hydration states—mono-, di- and trihydrates. MgO impurity is known to react with ibuprofen. In addition, magnesium stearate provides a basic pH environment, and may accelerate hydrolytic degradation.The magnesium metal may also cause chelation-induced degradation


6

Table 3. Interaction and incompatabilities of the excipients with functional groups and different types of reaction

Sr. no. Functional group Incompatibilities Type of reaction

1 Primary amine Mono and disaccharides

Amine-aldehyde and amine-acetal

2 Ester, cyclic lactose Basic components Ring opening, ester-base, hydrolysis

3 Carbonyl, hydroxyl Silanol Hydrogen bonding

Silanol Hydrogen bonding

4 Aldehyde Amine, carbohydrates Aldehyde-amine, Schiff base or glycosylamine formation

5 Carboxyl Bases Salt formation

6 Alcohol Oxygen Oxidation to aldehydes and ketones

7 Sulfhydryl Oxygen Dimerization

8 Phenol Metals Complexation

9 Glelatin capsule shell Cationic surfactants Denaturation

Table 4. Analytical techniques used to characterize drug/excipient compatibility

Sr. no.

Investigative

technique

Measurement Utility of data

1 DSC Energy is absorbed or released by a sample as it is heated, cooled, or held at a constant

Temperature

Physicochemical compatibility of drug and Excipients

2 TGA Weight changes by a sample as it is heated, cooled, or held at a constant temperature

Physicochemical compatibility of drug and Excipients

3 Chromatographic

analysis

Chemical interactions of the sample with the stationary phase and the mobile phase

Excipients, drug product purity; excipient–drug substance chemical compatibility

4 Microcalorimetry Absorbance or release of heat from solution sample

Physicochemical compatibility of drug and excipients; solution applications

5 X-ray diffraction Scattering of x-ray radiation by a solid sample

Polymorph characterization

6 Microscopy Magnified appearance of sampl Particle size, morphology

7 LC-MS/MS Chromatographic separation and fragmentation of molecular species

Impurity, degradation product identification

1.5 Interaction and Incompatabilities of the Excipients with Functional Groups [4]

Different excipients have different chemical nature, different functional groups and different reactivity towards other functional groups of drug or excipients Table 3. shows interaction and incompatabilities of the excipients with functional groups and different types of reaction which was observed commonly.

1.6 In Table 4, the Utility of Some of the Analytical Techniques Used to Characterize Drug/Excipient Compatibility are Listed [5]

In this present review article, we discussed about different categories of drugs and commony used excipient in it’s formulations. Excipients interactions and drug degradation due to Lactose, Magnesium stearate, Polyethylene glycol, Citric acid, Fumaric acid, Formaldehyde,


7

Starch, Titanium dioxide, Oleic acid and Polyvinyl pyrolidone were explained.

2. SACCHARIDES

2.1 Lactose Lactose disaccharide reducing sugar is the most commonly used excipients in various pharmaceutical oral unit dosage forms but potentially react with drugs containing amino

groups. The sequence of such reaction is referred to as the Maillard reaction. The literature survey reveals the incompatibility of lactose with amine-containing APIs. Micheal addition reaction with primary amine result in formation of 1-4 addition products between the drug and the maleic acid propogated by the free moisture associated with the starch. Pregelatinized starch showed Such type of formation of the 1,4-addition reaction which finally leads to the formation of maillard reaction product [6].

CO2

OH

OH OOH

OHOH

+ Pr-NH2

OH2

OH

OH NH-PrOH

OHOH

Glucose Schiff base

OH

OH NH-PrOH

OHOHOH

OH NH-PrOH

OOHOH

OH NH-PrOH

OHOH

CH2OH

OH O

OHOH

OH

OH O

OHOH

CH3

R1

OO

R2

OH

OH N-Pr

OHOH

OH2

OH

OH OH

OOH

O

NH2-Pr

OH2

1,2 - enaminol

3- deoxyosone

a-dicarbonyl

AGE PRODUCTS

2,3 - enaminol

1- deoxyosone

CH3

COOH

NH2

Amino acid

NH2-Pr+

Several steps

AGE PRODUCTS

Amadori product

Several steps

N

COOH

NH2

R3

O

R1

R2

N

OH

R2

R1

R3

NH

OH

R2

R1

R3 OH

R3 O

OH

R2

R1

NH2

OH2

Several steps

Strecker aldehyde

Further downstream processes

Fig. 3. Simplified scheme of the Maillard reaction


8

The mechanism of the Maillard reaction is very complicated; however, it is generally divided into three stages.

1) The first stage involves the sugar-amine condensation and the Amadori rearrangement. The reaction steps have been well-defined and no browning occurs at this stage.

2) The second stage involves sugar dehydration and fragmentation, and amino acid degradation via the Strecker reaction especially at high temperatures.

3) Formation of heterocyclic nitrogen compounds. Browning occurs at this stage. [7,8].

2.2 Baclofen Maillard reaction between Lactose and Baclofen were characterized by HPLC, LC-MS/MS and FT-IR. Mass spectrum shows 4 peaks.Unknown 1

st impurity is of Baclofen- Lactose

adduct,Unknown 2nd

impurity of lactose condensation reaction result in formation of baclofen–galactose or baclofen–glucose adducts. There are two major impurities in baclofen powder, 3

rd of them is an oxopentanoic

acid derivative: (3R,S)-5-amino-3-(4-chlorophenyl)-5-oxopentanoic acid and 4th contains a lactam ring and is named (4R,S)-4-(4-chlorophenyl) pyrrolidin-2-one.The FT-IR data shows the first step of the Maillard reaction leads

OH

NH2

O

Cl

O

OH

OH

OH

OOH

OH

OH

O

OH

OH

+

OH

OH

OH

OH

OOH

OH

OH

O

OH

OH

OH

NH

O

Cl

OH

OH

OH

OH

OOH

OH

OH

O

OH

OH

N

O

ClMolecular Formula :

C10H12ClNO2

Nominal Mass value : 213.66

Baclofen

Molecular Formula :

C12H22O11


Lactose

Molecular Formula :

C22H34ClNO13


Condensation product

Molecular Formula :

C22H32ClNO12


Proposed Unknown - 1

Fig. 4. Formation of 1st unknown impurity from baclofen and lactose Maillard reaction

(Baclofen - lactose adduct)

O

OH

OH

OH

OH OHOH

NH2

O

Cl

OH

OH

OH

OH

OH

NH

O

Cl

OH

+

OH

OH

OH

OH

OH

N

O

Cl

OH

Molecular Formula :

C10

H12

ClNO2


Baclofen

Molecular Formula :

C6H

11O

6


Galactose

Molecular Formula :

C16

H24

ClNO8


Condensation Product

Molecular Formula :

C16H22ClNO7


Proposed Unknown-2

Fig. 5. Formation of 2

nd unknown impurity from galactose and baclofen Maillard reaction

(Galactose- baclofen adduct)


9

to the formation of an imine known as a Schiff’s base. In the baclofen FTIR spectrum,Adduct mixtures showed C=N stretching indicating convertion of imine into its isomeric enamine form during the Maillard reaction [9]. 2.3 Doxepin Physicochemical incompatibility of doxepin with dextrose was evaluated in solid-state mixtures and the compatibility was characterized by using different physicochemical methods such as DSC, Fourier transform infrared spectroscopy and mass spectrometry. The melting endothermic peak of doxepin hydrochloride was disappeared in the doxepin hydrochloride–dextrose binary mixture and the dissolution of the drug particles inside the melted excipients and a new peak appeared due to incompatability.IR spectra of Dextrose–doxepin hydrochloride showd a new peak at 1647 cm-1,due to C=N covalent band indicating incompatibilitydue to Maillard-type reaction.The full-scan positive-ion electrospray product ion mass spectra showed that the molecular ion of doxepin hydrochloride was a protonated molecules, formed condensation

product B and Amadori rearrangement product labeled as condensation product-A [10].

2.4 Fluoxetine

Drugs which contains secondary amines also can undergo the Maillard reaction with lactose under pharmaceutically relevant conditions. Fluoxetine was characterized by NMR, GC-MS,HPLC. The fluoxetine undergo Maillard reaction and formed N-Formylfluoxetine as a major product. Also GC/MS characterization study reported various characteristic volatile products of the Maillard reaction, including furaldehyde,maltol, and 2,3-dihydro-3,5-dihydroxy-6-methyl 4H-pyran-4-one [11].

2.5 Memantine

Maillard reaction of Memantine identified by gradient high performance liquid chromatographic (HPLC) method using charged aerosol detection (CAD). Reported impurities are memantine-lactose adduct (ML), a memantine-dimethylamino glycine adduct (DMAG), a memantine-galactose adduct (MGAL) and a memantine-glucose adduct (MGLU) [12].

O

OH

OH

OH

OH

OH

O

NCH3

CH3

+

OH

OH

OH

OH

OH O

N

H

O+

H

O+

OH

OH

OH

OH

O

NH

H

Molecular Formula : C23H27NO7

Average Mass : 429.463 Da

Condensation product-A

Molecular Formula : C23H27NO6


Condensation product -B

Molecular Formula :

C6H12O6


Molecular Formula :

C19H21NO


Fig. 6. Proposed structures for Maillard reaction of doxepin hydrochloride with dextrose

ClHNH

O

CH3

CF3

Fluoxetine HydrochlorideAmadori Rearrangement product

Heat

N

O

CF3

CH3

OH

N-formylfluoxetine

Lactose

OH

O

OH

OOH

OH

OH

O

OH

N O

CF3

CH3

OH

Fig. 7. Maillard reaction of lactose and fluoxetine HCl


10

O

OH

OH

OH

OOH

OH

OH

O

OH

CH3

NH

CH3

Glycosylamine

NH

CH3

OOH

OH

OH

O

OH

O

OH

OH OH

Amadori Rearrangement product (ARP)Memantine-Lactose adduct(ML)

CH3

NHO

OH

OH

OH

H

H

OHH

CH3

Memantine-Galactose Adduct (MGAL)

CH3

NHO

OH

OH H

OH

OHH

CH3

H

Memantine-Glucose adductMGLU product

CH3

NH

CH3

OH

O

Memantine-DimethylaminoGlycine Adduct (DMAG)

CH3

CH3

NH2O

OH

OH

OH

OOH

OH

OH

O

OH

OH

Galactose GlucoseMemantine

+

- H2O+ H2O

Β- Lactose

Fig. 8. Schematic diagram showing Maillard reaction between lactose and memantine

2.6 Sitagliptin

Formation of the imine bond with sitagliptin found in the presence of lactose (the Maillard reaction) at high temperature and high humidity and it is characterized by FTIR and LC-MS. In LC-MS characterization other various degradation products were found [13].

2.7 Abacavir

Two newer interaction products (ALm 1 and ALm 2) generated due to reaction between Abacavir and lactose which was characterized by hyphenated analytical techniques like LC-

MS/TOF and NMR, further evaluated using in silico drug designs, in-silico toxicity and ADMET properties, whereas interaction products were analysed using TOPKAT and ADMETTM software and compared to the drug [14].

2.8 Nebivolol

Nebivolol (NEB)–lactose adduct formed in unbuffered solution, buffered alkaline solutions and dry physical mixture and Maillard adduct characterized by FTIR, HPLC and LC-MS. Due to adduct formation of the NEB–lactose adduct results in highly significant loss in the bradycardic effect of NEB [15].


11

N

NN

N

NH2

F

F

F

O

CF3

Sitagliptin

O

OH

OH

OH

OOH

OH

OH

O

OH

OH

+

O

OH

O O

OH

OH

OH

OH OH

OH

N

NN

N

NH

F

F

F

O

CF3

Lactose

Unknown impurity

Fig. 9. The Maillard reaction between the NH2 group of sitagliptin and lactose

O

O

OH

OH

OH

OH

O

OH OH

CH3

NH

N

N

N

N

NH

OH

ALm 1

O

OH OH

CH3

NH

N

N

N

N

NH

OH

OH

ALm 2

Fig. 10. Abacavir and lactose interaction products ALm1 and ALm2

OH

OH

OHO

OH

OH

OH

O

OH

OH

O

N+

O

OH

OH

F

F

H

H

H

OH

OH

Molecular Formula =

C36H52FNO16+

Average Mass =792.79DaCondensation product

OH

OH

OH

OHO

OH

OH

OH

O

OH

OH

O

N+

O

OH

OH

F

F

H

H

Molecular Formula =

C36H50F2NO15+

Average Mass =774.77 DaProposed structure for adduct

Fig. 11. Proposed Maillard reaction condensation products of NEB and lactose


12

N

O

O

CH3

CH3CH3

NH

O O CH3

OHO

O

N

O

O

CH3

CH3CH3

NH

O OH

OHO

O

N

O

O CH3

O

N

O O

CH3

O

CH3

CH3

Hydrolysis product - Moexiprilate

M=470;ES+ m/z = 471; ES- m/z=469

Cyclization product- Diketopiperazine derivative of Moexipril

M=480;ES+ m/z = 481

Moexipril

M =498;ES+ m/z = 499; ES- m/z=497

-28

-18

Fig. 12. The proposed scheme for degradation of moexipril hydrochloride in the presence of

magnesium stearate (RH 76.4% and T = 318K)

NHN

O O

OOH

CH3

CH3

O

NHN

O OH

OOH

CH3

O

N

O O

CH3

CH3

NO

O

Enalapril

M=376;ES+ m/z = 377 ; ES-

m/z=375

Hydrolysis product Enalaprilate

M=348;ES+ m/z = 349; ES- m/z=347

Cylization product-Diketopiperazine derivative of Enalaprilate

M=358;ES+ m/z = 359; ES- m/z=357

Fig. 13. The proposed scheme for degradation of enalapril maleate in the presence of magnesium stearate (RH 76.4% and T = 318K)


13

N

N

NH

OOH

OO

CH3

CH3

O

HCH3

H

O

N

N

NH

OOH

OOHCH3

O

HCH3

H

O

Imidapril Hydrochloride

Hydrolysis

ClH

Hydrolysis product of Imidapril

Fig. 14. The proposed scheme for degradation of imidapril hydrochloride in the presence of

magnesium stearate (RH 76.4% and T = 318K)

NHN

O OH

OOH

NH2

O

N

O OH

NH2

N

O

O

Lisinopril

M=405;ES+ m/z = 406; ; ES-

m/z=404

Cyclization product - Diketopiperazine derivative of Lisinopril

M=387;ES+ m/z = 388; ES- m/z=386

Cyclization

H2O

Fig. 15. The proposed scheme for degradation of lisinopril in the presence of magnesium

stearate (RH 76.4% and T = 318K)

3. MAGNESIUM STEARATE

Magnesium stearate is the salt of a complex mixture of fatty acids, with the main component as stearate and palmitate. It has multiple crystalline forms and an amorphous form [16]. Various researchers reported magnesium incompatibilitywith drug.

3.1 Moexipril Hydrochloride (Moxl), Imidapril Hydrochloride (Imd), Enalapril Maleate, (Ena) and Lisinopril (Lis) in Solid State with Magnesium Stearate

Incompatibilitybetween moexipril hydrochloride (MOXL), imidapril hydrochloride (IMD), enalapril maleate, (ENA) and lisinopril (LIS) in solid state with magnesium stearate noticed when

Magnesium stearate and drugs undergo hydrolysis and cyclization to give various drug degradation products [17].

4. PEG In many literature authors revealed that polyoxyethylene linkages containing substances such as polysorbate surfactants, poloxamers, and PEGs undergo auto-oxidation, resulting in the formation of hydroperoxides and peroxide-free radicals. Steps in Auto-oxidation reaction of PEG Catalyzed by metal- and/or light-induced

decomposition of polyoxyethylene chains.

Chain eaction propogation by consumption of oxygen and formation of hydroperoxides


14

Reaction termination by the decomposition of hydroperoxides and/or collision among free radicals.

Peroxides and other oxidizing species such as peroxide and hydroxyl radicals, in formulations containing low levels of residual peroxides, can thus lead to fast degradation of the active drug resulting in significantly compromised therapeutic activity [18].

4.1 Cetrizine Oxidative degradation of cetirizine occurs in polyethylene glycol. The reaction between the drug and the reactive peroxide intermediates such as peroxyl radicals formed through

oxidation of PEG. Oxidation of cetirizine produce as cetirizine N-oxide as degradation product [19]. Cetirizine and PEG undergo esterification due to free carboxylic group and formation of Cetirizine PEG Esters, and Di-Cetirizine PEG Esters [20].

4.2 Indomethacine The esterification of Indomethacine with PEG leads to formation of esterified products such as PEG esters of indomethacin and di-indomethacin PEG esters. The reported two hydrolysis products [5-methoxy-2-methyl-1H-indol-3-yl] acetic acid and 4-chloro-benzoic acid as well as their PEG ester was also reported [20].

N N

O O

OH

Cl

OH OH

N N+

O O

OH

Cl

O

H

OH–

N N+

O O

OH

Cl

O–

+ H2O

Fig. 16. Proposed mechanism for the oxidation of cetirizine to form N-oxide

N

N

O

O

O

ClO

N

N

O Cl

O

N

N

O

O

OH

Cl

+ OOHCH3

n

N

N

O

O

O

Cl OH

+

n

H2O

Cetrizine, Mexact= 388.16 Da

PEG

Cetrizine PEG esters

Di-Cetrizine PEG esters

Fig. 17. Structure of cetirizine, PEG, cetirizine PEG esters and di-cetirizine PEG esters


15

OO

N

N

H3COH3CO

Cl

Cl

O

O

O

O

N

O

O

OH

Cl

H3CO

CH3

O

OHH

n

+N

OO

Cl

O

CH3

OOH CH3

+

Di-Indomethacine PEG esters

Indomethacine ,Mexact = 357.08

Da

PEGIndomethacine PEG esters

NHO

O

CH3

CH3O

OH

CH4

PEG (5-Methoxy- 2- methyl 1H- indol- 3- yl- acetate )

+ OH2

OH2

Fig. 18. Structure of indomethacin, PEG and PEG esters of indomethacin and di-indomethacin PEG esters. In addition, the structures of the two hydrolysis products [5-methoxy-2-methyl-1H indol-3-yl] acetic acid and 4-chloro-benzoic acid as well as their PEG ester reaction products

are presented

5. CITRIC ACID In various formulations Citric acid used for pH stabilizer.Drug release rates and absorption were different at different pH level [14]. But some times it also react with drug components [21].

5.1 Carvedilol and Codeine Phosphate Esterification of Carvedilol (CAR) and Codeine Phosphate (COP) with citric acid (CA) alter drug biological action. Due to mechano-activation means co-milling of API and Citric acid causes faster reaction than in physical powder mixtures kept at accelerated storage conditions. It is characterized by thermal behavior in DSC, their

SWAXS patterns and also by characteristic peaks in the Raman fingerprint region-Raman spectra [22].

6. FUMARIC ACID In some formulations Fumaric acid used to improve stability and moisture sensitivity via the dry granulation. It was observed that slow dissolution kinetics of fumaric acid prolongs an acidic microenvironment around the API granules and excipients leading to increased dissolution and increased absorption [23]. But due to fumaric acid, some drug excipient incompatibility found in formulations.


16

NH

O

NH

OH

O

OCH3

+ CH3 CH3

O

OH

O

OH

OOOH OH

NH

O

NH

O

O

OCH3

OH

O

NH

O

NH

O

O

OCH3

OHO

O

OH

OOH Fig. 19. Esterification reactions of carvedilol with citric acid

O

N CH3

OCH3

OH

H

+ CH3 CH3

O

OH

O

OH

H2

O

N CH3

OCH3

O

H

OH

O

HO

OHO

OH

H2

N CH3

OCH3

O

H

O

O

OHO

CH3

OH

Fig. 20. Esterification reactions of codein phosphate and citric acid

N

NN

N

NH2

F

F

F

O

CF3

OHOH

O

ON

NN

N

NH

F

F

F

O

CF3

OHOH

O

O

+

Sitagliptin Fumaric acid

Michael addition product

Fig. 21. Interactions between the NH2 group of sitagliptin and the double bond of fumaric acid

(The Michael addition)

6.1 Sitagliptin

Degradation of sitagliptin in fumaric acid occurs at highly stressed condition. The amino group of sitagliptin and double bond of fumaric acid undergo Michael addition reaction to form unknown sitagliptin-lactose adduct. It is characterized by LC-MS,FTIR [13].

7. FORMALDEHYDE

Formaldehyde and other aldehydes are known impurities in several excipients such as Starch, degradation product of lactose, Povidon and

cross Povidon, packaging components. Formaldehyde reacts with amine functional group of drugs to form N-formyl adducts (hemiaminals) that can further react to form dimer [24].

7.1 Amlodipine New unknown impurity were observed during the accelerated stability analysis in the multicomponent tablets of amlodipine besylate. This formed impurity characterized by UHPLC-MS and NMR techniques.The reported degradation product of amlodipine besylate as


17

NH

O

N+

HH

CH3

O

O

CH3

O

CH3

O Cl

Chemical structure :-

C21H26CIN2O5

Exact Mass:- 421.1525

NH

O

N

H

CH3

O

O

CH3

O

CH3

O Cl

Chemical Formula :- C21H25ClN2O5

Exact Mass :-421.15Unknown impurity : 3-ethyl 5-methyl 4-(2-chlorophenyl)-6-methyl-2-(morpholin-2-yl)-1,4-dihydropyridine-3,5-dicarboxylate

Fig. 22. The proposed unknown impurities of amlodipine

3-ethyl 5-methyl 4-(2-chlorophenyl)-6-methyl-2-(morpholin-2-yl)-1,4-dihydropyridine-3,5-dicarboxylate [25].

8. STARCH Chemically, starches are polysaccharides, contains monosaccharides or sugar (glucose) molecules linked together with α-d-(1-4) and/or α-d-(1-6) linkages. Starch has been used as excipient in many novel drug delivery systems which acts as disintegrants, fillers or binders. Due to its partial cold water solubility, performs dual functions of both a disintegrant and a binder and in capsule filling processes, Starch and Star Cap Co-Processed Starch Excipients used as binders. As a result of its partial cold water solubility, starch functions exceptionally well in tablet manufacture by wet granulation applications and performs dual functions of both a disintegrant and a binder. In capsule filling processes, Starch function as effective binders [26]. 8.1 Seproxetine Seproxetine maleate hemihydrate salt, a selective serotonin re-uptake inhibitor, showed incompatibilitybetween primary amine containing active metabolite of fluoxetinen with lactose and

starch in a gelatin capsule dosage form. It undergoes Micheal addition to form 1-4 addition product in the presence of pregelatinized starch while a Maillard reaction product was formed [6]. 9. TITANIUM DIOXIDE Titanium dioxide specimens like Wackherr TiO2, prepared TiO2 and Aeroxide P25 toward the photocatalytic synthesis widely used in pharmaceuticales. TiO2 Wackherr has low cost than other therefore more useful when high photocatalyst loading is required at high substrate concentration. But periodically it causes incompatibilitywith drugs [27].

9.1 Metoprolol The comparision between photocatalytic activity of TiO2 Wackherr and TiO2 Degussa P25 under UV irradiation. Under UV, the process involving TiO2 Wackherr significantly showed faster photocatalytic activity than direct photolysis. The Transformation with Degussa P25 it is due to the higher radiation scattering by Degussa P25 compared to TiO2 Wackherr ensures that the former photocatalyst is less efficient in using radiation. Fourteen intermediates were identified by LC–MS/MS (ESI+).

N

N

NHNH2

+ RCHO N

N

NH N

R

N

N

NN

R

Starch

Fig. 23. Reaction of hydralazine with terminal aldehydes of starch residue


18

O

CF3

NH2

H+

OH

OH

O

OH

Starch O

CF3

NH

H

OH

OH

O

OH

O

CF3

NH

H

OH

OH

O

OH

Seproxetine Maleic acid

1,4 - Addition product

Fig. 24. Interaction between seproxetine and maleic acid in the presence of starch

O

OCH3

OH

NH CH3

CH3

O

OCH3

OH

NH CH3

CH3

(OH) 3

O

O

O

NH CH3

CH3OH

NHCH3

CH3

OH

O

O

OH

O

OCH3

OH

N CH3

CH3

CH3Metoprolol

Unknown A

Unknown B

Unknown C

Fig. 25. The photocatalytic degradation products of MET. Note that a was only identified with TiO2 Wackherr, B and C only with Degussa P25


19

Characterization by LC-MS/MS involved photocatalytic degradation process like Hydroxylation of the aromatic ring, Shortening of the methoxyl containing

lateral chain, Cleavage of, or addition of •OH to, the

amine-containing one. [28]

10. OLEIC ACID Oleic acid (OA), commonly used as vehicle in many pharmaceuticals. OA added in the formulations to increase drug solubility. But during purification by aid of distillation, dehydrated oleic acid formation leads to incompatibility between drugs and excipient.

10.1 WR 30090 (Mefloquine and Halofantrine Analog)

Incompatibility between novel antimalarial WR 30090 an analog of mefloquine and hal of antrine were observed when it formulated in a high purity sample of oleic acid as the vehicle. WR 30090 showed considerable chemical instability to form Oleic acid ester of WR 30090.It was due to oleic acid anhydrate which was prepared by fraction distillation of oleic acid.

The lipid lowering agent, 3-(2,4 diflurophenyl)-1-heptyl- 1-(neopentylbenzyl)urea (3), also formulated with oleic acid. On storage 3 rapidly degraded to a complex mixture with two of the degradation products identified shown in Fig. 26 [29].

N

NC4H9

C4H9

OH

Cl

Cl

Cl

Cl

Oleic Acid

N

NC4H9

C4H9

O

Cl

Cl

Cl

Cl

(CH2)6(CH2)6 CH3

12

Fig. 26. Reaction pathway for the degradation of WR 30090 in an oleic acid vehicle (1), possibly

due to oleic acid anhydride in the purified oleic acid sample

NH N

O

F

F

CH3

CH3

CH3

CH3

Oleic Acid

NH NH

FF

O

FF

3- ( 2,4- diflurophenyl)- 1- (4- neopentylbenzyl ) urea

3

Fig. 27. Some degradation products seen when 3-(2,4-diflurophenyl)-1-heptyl-1

(neopentylbenzyl)urea (3) was formulated with oleic acid (2)


20

S

O N

OH

O

OH

ClH

OH O R

Peroxides from excipients( Povidone ) in formulation

S

O N+

OH

O

OH

OH

ClH

Raloxifen hydrochloride Raloxifen N- Oxide

+ ROH

Fig. 28. Excipient-induced (Povidone and crospovidone) oxidation of a tertiary amine Raloxifene hydrochlorid [31]

11. PVP

Nitrates, nitrites are common nitrosating impurities that can be found in most excipients at parts per million (ppm) levels. Sodium starch glycolate, croscarmellose sodium, pre-gelatinized starch, PVP, cPVP. Many literature revealed that it also contain peroxides. The drugs containing functional groups that can potentially form NOCs with PVP, cPVP include dialkyl, alkylaryl, diaryl, cyclic secondary amines, N-alkylureas, N-alkylcarbamates and N-alkylamides to synthesize nitrosamines or nitrosamides products. To a much lesser extent, tertiary amines, cyanamides, guanidines, amidines, hydroxylamines, hydrazines, hydrazones and hydrazides may also form NOCs [24].

11.1 Raloxifen N-oxidative degradation product of raloxifene and povidon and crospovidone were observed [30].

12. CONCLUSION Structure characteristics like molecular functional groups, their reactivity and chemical nature of the molecules and excipients shall be considered in predicting the drug excipient interactions and compatability. Drug, excipients degradated product, susceptible degradation factors such as micro environmental factors, metal ion, storage conditions, impurities, peroxide content and manufacturing details should be checked and ensured before finalizing the excipients. This article gives an idea about how the reactive functional groups in drugs will react with

excipients in drug formulation. Best excipient, storage conditions and its prevention of drug excipient interaction establishing the good formulation. Advanced analytical development should ensure any unknown peaks formed during the drug excipient compatibility studies helps to ensure drug compatibility. Thorough monitoring and prevention of unknown impurities and its origin during drug development process reduces the delay in the product filings and USFDA approvals.

COMPETING INTERESTS Authors have declared that no competing interests exist.

REFERENCES 1. Haywood A, Glass BD. Pharmaceutical

excipients – Where do we begin. Aust Prescr. 2011;34 (4):112-4. DOI: 10.18773/austprescr.2011.060

2. Narang AS, Rao VM, Raghavan KS. Excipient compatibility. In developing solid oral dosage forms. Academic Press. 2009:125-45.

3. Jinnawar KS, Gupta KR. Drug excipient compatibility study using thermal and non-thermal methods of analysis. Int J Chem tech Applications. 2012;2(2):23-49.

4. Keraliya vipul. Drug-excipient compatibility studies. Available:http://pharmaquest.weebly.com/uploads/9/9/4/2/9942916/drug_excipient_compatibility_study.pdf (Accessed on: 16 July 2019)


21

5. DiFeo TJ. Drug product development: A technical review of chemistry, manufacturing and controls information for the support of pharmaceutical compound licensing activities. Drug development and industrial pharmacy. 2003;29(9):939-58. Available:https://doi.org/10.1081/DDC-120025452

6. Bharate SS, Bharate SB, Bajaj AN. Interactions and incompatibilities of pharmaceutical excipients with active pharmaceutical ingredients: A comprehensive review. Journal of Excipients and Food Chemicals. 2016;1(3): 1131.

7. Lund MN, Ray CA. Control of Maillard reactions in foods: Strategies and chemical mechanisms. Journal of Agricultural and Food Chemistry. 2017;65 (23):4537-52. Available:https://doi.org/10.1021/acs.jafc.7b00882

8. Mauron J. The Maillard reaction in food. Prog. Fd. Nutr. Sci. 1981;5:5-35.

9. Monajjemzadeh F, Hassanzadeh D, Valizadeh H, Siahi-Shadbad MR, Mojarrad JS, Robertson T, Roberts MS. Assessment of feasibility of Maillard reaction between baclofen and lactose by liquid chromatography and tandem mass spectrometry, application to pre-formulation studies. AAPS Pharm Sci Tech. 2009;10(2):649-59. Available:https://doi.org/10.1208/s12249-009-9248-8

10. Ghaderi F, Nemati M, Siahi-Shadbad MR, Valizadeh H, Monajjemzadeh F. DSC kinetic study of the incompatibility of doxepin with dextrose. Journal of Thermal Analysis and Calorimetry. 2016; 123(3):2081-90. Available:https://doi.org/10.1007/s10973-015-4995-0

11. Wirth DD, Baertschi SW, Johnson RA, Maple SR, Miller MS, Hallenbeck DK, Gregg SM. Maillard reaction of lactose and fluoxetine Hydrochloride, a secondary amine. Journal of Pharmaceutical Sciences. 1998;87(1):31-9. Available:https://doi.org/10.1021/js9702067

12. Rystov L, Chadwick R, Krock K, Wang T. Simultaneous determination of Maillard reaction impurities in memantine tablets using HPLC with charged aerosol detector. Journal of Pharmaceutical and Biomedical Analysis. 2011;56(5):887-94.

Available:https://doi.org/10.1016/j.jpba.2011.07.010

13. Gumieniczek A, Berecka A, Mroczek T, Wojtanowski K, Dąbrowska K, Stępień K. Determination of chemical stability of sitagliptin by LC-UV, LC-MS and FT-IR methods. Journal of Pharmaceutical and Biomedical Analysis. 2019;164:789-807. Available:https://doi.org/10.1016/j.jpba.2018.11.023

14. Kurmi M, Sahu A, Ladumor MK, Bansal AK, Singh S. Stability behaviour of antiretroviral drugs and their combinations. 9: identification of incompatible excipients. Journal of Pharmaceutical and Biomedical Analysis. 2019;166:174-82.

15. Patil DD, Patil CR. Modification of pharmacological activity of nebivolol due to Maillard reaction. Pharmaceutical Development and Technology. 2013;18(4): 844-51. Available:https://doi.org/10.3109/10837450.2011.591802

16. Delaney SP, Nethercott MJ, Mays CJ, Winquist NT, Arthur D, Calahan JL, Sethi M, Pardue DS, Kim J, Amidon G, Munson EJ. Characterization of synthesized and commercial forms of magnesium stearate using differential scanning calorimetry, thermogravimetric analysis, powder X-ray diffraction and solid-state NMR spectroscopy. Journal of Pharmaceutical Sciences. 2017;106(1):338-47. Available:https://doi.org/10.1016/j.xphs.2016.10.004

17. Stanisz B, Regulska K, Kania J, Garbacki P. Effect of pharmaceutical excipients on the stability of angiotensin-converting enzyme inhibitors in their solid dosage formulations. Drug Development and Industrial Pharmacy. 2013;39(1):51-61. Available:https://doi.org/10.3109/03639045.2012.657644

18. Kumar V, Kalonia DS. Removal of peroxides in polyethylene glycols by vacuum drying: Implications in the stability of biotech and pharmaceutical formulations. AAPS Pharmscitech. 2006;7 (3):E47. Available:https://doi.org/10.1208/pt070362

19. Dyakonov T, Muir A, Nasri H, Toops D, Fatmi A. Isolation and characterization of cetirizine degradation product: Mechanism of cetirizine oxidation. Pharmaceutical Research. 2010;27(7):1318-24.


22

Available:https://doi.org/10.1007/s11095-010-0114-x

20. Schou‐Pedersen AM, Hansen SH, Moesgaard B, Østergaard J. Kinetics of the esterification of active pharmaceutical ingredients containing carboxylic acid functionality in polyethylene glycol: Formulation implications. Journal of Pharmaceutical Sciences. 2014;103(8): 2424-33. Avaialble:https://doi.org/10.1002/jps.24062

21. Nykänen P, Lempää S, Aaltonen ML, Jürjenson H, Veski P, Marvola M. Citric acid as excipient in multiple-unit enteric-coated tablets for targeting drugs on the colon. International Journal of Pharmaceutics. 2001;229(1-2):155-62. Available:https://doi.org/10.1016/S0378-5173(01)00839-0

22. Gressl C, Brunsteiner M, Davis A, Landis M, Pencheva K, Scrivens G, Sluggett GW, Wood GP, Gruber-Woelfler H, Khinast JG, Paudel A. Drug–excipient interactions in the solid state: The role of different stress factors. Molecular Pharmaceutics. 2017;14 (12):4560-71. Available:https://doi.org/10.1021/acs.molpharmaceut.7b00677

23. Menning MM, Dalziel SM. Fumaric acid microenvironment tablet formulation and process development for crystalline cenicriviroc mesylate, a BCS IV compound. Molecular Pharmaceutics. 2013;10(11):4005-15. Available:https://doi.org/10.1021/mp400286s

24. Wu Y, Levons J, Narang AS, Raghavan K, Rao VM. Reactive impurities in excipients: Profiling, identification and mitigation of drug–excipient incompatibility. AAPS Pharm Sci Tech. 2011;12(4):1248-63. Available:https://doi.org/10.1208/s12249-011-9677-z

25. Gibala P, Douša M, Kalužíková A, Tkadlecová M, Štefko M, Kalášek S, Břicháč J. Identification and structure elucidation of a new degradation impurity

in the multi-component tablets of amlodipine besylate. Journal of Pharmaceutical and Biomedical Analysis. 2019;162:112-6. Available:https://doi.org/10.1016/j.jpba.2018.07.040

26. Barmi Hartesi1,2, Sriwidodo2, Marline Abdassah2, Anis Yohana Chaerunisaa. Starch as pharmaceutical excipient. Int. J. Pharm. Sci. Rev. Res. 2016;14: 59-64.

27. Selvam K, Swaminathan M. Photocatalytic synthesis of 2-methylquinolines with TiO2 Wackherr and home prepared TiO2 – A comparative study. Arabian Journal of Chemistry. 2017;10:S28-34. Available:https://doi.org/10.1016/j.arabjc.2012.07.001

28. Abramović B, Kler S, Šojić D, Laušević M, Radović T, Vione D. Photocatalytic degradation of metoprolol tartrate in suspensions of two TiO2-based photocatalysts with different surface area. Identification of Intermediates and Proposal of Degradation Pathways. Journal of Hazardous Materials. 2011;198: 123-32. Available:https://doi.org/10.1016/j.jhazmat.2011.10.017

29. Misic Z, Jung DŠ, Sydow G, Kuentz M. Understanding the interactions of oleic acid with basic drugs in solid lipids on different biopharmaceutical levels. Journal of Excipients and Food Chemicals. 2016;5(2): 950.

30. Yarkala S, Amaravadi S, Rao VU, Navalgund SG, Jagdish B. Role of excipients on N-oxide raloxifene generation from raloxifene–excipients binary mixtures. Chemical and Pharmaceutical Bulletin. 2009;57(10): 1174-7. Available:https://doi.org/10.1248/cpb.57.1174

31. Baertschi SW, Alsante KM. Stress testing: The chemistry of drug degradation. In Pharmaceutical Stress Testing. CRC Press. 2016;61-153.

_________________________________________________________________________________ © 2019 Gupta et al.; This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Peer-review history: The peer review history for this paper can be accessed here:

http://www.sdiarticle4.com/review-history/51941

Drug Excipient Compatibility Testing Protocols and ...

Documents

Transcript of Drug Excipient Compatibility Testing Protocols and ...