How to Cite:

Ahmad, F., Akhlaq, S., Fiaz, I., Bhutto, A. A., Khan, I., Ajmal, A., & Ahmad, J. (2023).
Determination of scums in medicine materials. International Journal of Health
Sciences, 7(S1), 674–689. https://doi.org/10.53730/ijhs.v7nS1.14257

Determination of scums in medicine materials

Dr. Fiaz Ahmad

Assistant Professor, Ayub Teaching Hospital Abbottabad, Pakistan
Email: tanolilion@yahoo.com

Dr. Sana Akhlaq

MD, M. Phil Physiology, Medical College Gujranwala, Pakistan
Email: sanaasim83@gmail.com

Dr. Ilyas Fiaz

House Officer, Ayub Medical College Abbottabad, Pakistan
Email: Red39864@gmail.com

Ali Asghar Bhutto

Fresh Graduate Pharm-D from Liaquat University of Medical and Health Sciences
Jamshoro, Pakistan
Email: aliasgharbhutto7@gmail.com

Ijaz Khan
Master in Chemistry, Comsats University Islamabad, Pakistan
Email: kijaz689@yahoo.com

Amina Ajmal
Assistant Professor, Dental Section NIMS, Pakistan
Email: amnakayani072@gmail.com

Dr. Junaid Ahmad

Assistant Professor, Dental Section Nims, Pakistan
Email: juniadahmad73@gmail.com

Abstract---The current study is describing the main degrading scums

in bromazepam, diazepam, Cefixime trihydrate, cefazolin sodium,
simvastatin, and lovastatin, among other materials and manufactured
items. HPLC was used to characterize pharmaceutical substance
scums by comparing their retention lengths to reference standards.
Before deciding, they sorted all the material from its main scums.
Scums fell between 1.23 to 20.57 min, and parent compounds had try
values between 2.71 and 9.22. Thus, isolating and identifying these
compounds takes 20 minutes. This study identified parent
compounds and degradation products using HPLC after confirming
the European Pharmacopeial methodology. HPLC method validation

International Journal of Health Sciences ISSN 2550-6978 E-ISSN 2550-696X © 2023.

Manuscript submitted: 27 Jan 2023, Manuscript revised: 09 March 2023, Accepted for publication: 18 April 2023
674
 675

for parent pharmaceuticals and degradation scums examined

specificity, linearity, precision, and accuracy. The process can be
applied to commodities and waste products using each compound's
values for these qualities. 98%–102% of parent and scum materials
are recovered. The experimental technique repeats within 3%. In
compliance with pharmacopeial and regulatory norms, scums above
0.1% must be determined for pharmaceutical safety, efficacy, and
quality. It's vital due to the effects of packaging, transit, storage, and
manufacturer synthetic pathways. Adjuvants may cause degradation
scums. The selected drugs' raw material and finished product levels of
their main degrading scums were examined, and a concentration
range was provided. Original and produced drugs have acceptable
percentages. Both raw material and produced product degradation
scums exceed ICH and other regulatory thresholds. Differences in
synthesis methodologies, manufacturing processes, and drug-
excipient interactions may cause this. This material has been forced to
degrade to predict stress-induced degradation products. This study
includes hydrolysis in acid and alkali and H2O2 oxidation. Acid
solution degrades faster than alkaline medium (80 0C). Hydrolytic
cleavage, caused by pharmacological excipient interactions and
environmental factors, degrades these compounds. This study can
help formulators reduce deteriorating scums, improving product
quality and performance. Excipients and synthetic processes affect
scum development.

Keywords---determination, scums, medicine materials.

Introduction

To be considered an impurity, a chemical entity must be present in the drug

substance, excipient, or other additives to the drug products but not in the drug
substance itself [1]. Impurity, which can be defined as "any material that affects
the purity of the material of interest," [2] plays a significant role from a variety of
perspectives, including ethical, economic, competitive, safety, and efficacy. When
impurities can alter a dosage form's performance or stability, or when they can
cause toxicological issues, their regulation and monitoring become required. This
is because of chemical reactivity and physical changes to the systems. A drug's
purity can be improved by reducing contaminants not just at the point of release
but also by keeping degradants to a minimum over the drug's storage period.
Synthetic precursors, ancillary materials, intermediates, heavy metals, moisture,
and volatile solvents are typically targeted in proposed procedures for control.

Long-term degradation monitoring requires stability-indicating techniques that

can distinguish between the active ingredient and degradation products, process
contaminants, or other potential impurities. The purity profile of the final
products can be improved by beginning the synthesis with high purity ingredients
[3]. Controlling and monitoring contaminants is emphasized by a number of
pharmacopoeias and regulatory organizations. 3 Table 1 provides a summary of
the published recommendations for dealing with impurities from the International
676

Conference on Harmonization (ICH) [4-8] and the Food and Drug Administration
[9-10]. The United States Pharmacopeia (USP) has also placed an emphasis,
under general notices [11], on the regulation of foreign substances and other
contaminants. ICH, the FDA, and other organizations have amassed a lot of
information on pollutants. The synthesis of drug ingredients and drug products is
increasingly subject to titer constraints and stringent controls due to
advancements in technology, as mandated by the international regulatory
community, pharmacopoeias, and the multinational sponsors of regulated
products. These tendencies call for permanent adherence to the highest quality
standards. Guidelines on impurities in new drug products [6] require the
identification of degradation products detected at concentrations greater than t,
while guidelines on impurities in new drug substances [5] require the
characterization of impurities detected at concentrations greater than 0.1%
(depending on the daily dose, calculated using the response factor of the drug
substance).

Types of Impurities

Impurities may broadly be classified into three classes as given in Table 3 [1].
First, there are organic impurities, which can be anything from raw materials to
process byproducts to intermediates and even degradation products.
Salts, catalysts, ligands, and heavy metals or other residual metals are all
examples of inorganic impurities.
c) Production and/or recrystallization residual solvents (organic and inorganic
liquids).

Table Impurity descriptions

Impurity Type Impurity Source

Process-relateddrug substance Organic
Starting material Intermediate#
By-product
Impurityinstartingmaterial
Process-relateddrug substance Organic or inorganic
reagents, catalysts,etc.
Degradation drug substance or drug Organic
product Degradationproducts
Degradation drugproduct Organic
Excipient interactionproducts

Aims and Objectives of Present Investigation

Drug substances and drug products may have impurities due to

contamination during manufacturing or degradation due to poor storage
conditions. Different synthesis techniques and starting
materials/intermediates can result in a wide range of contaminants. The
pharmacopoeias, ICH, FDA, and other regulatory bodies have all set maximum
allowable concentrations for contaminants, related compounds, and
degradation products in pharmaceuticals. Diazepam, bromazepam, cefixime,
cefazolin, simvastatin, and lovastatin are just few of the medications that
 677

would be tested for and analyzed for serious contaminants as part of this
project.

Synthetic medications are commonly prescribed for a wide range of medical

conditions. All of these medications are vulnerable to degrading impurity
caused by oxidation and hydrolysis. The parent chemicals' potency, safety, and
efficacy could be affected by these degrading impurities. These degradative
processes leading to contaminants could have been caused by the synthesis
method, ambient conditions, or formulation procedures.The purpose of this
research is to confirm the purity of pharmacological compounds made by
various manufacturers using potentially different synthetic techniques. The
material's impurities and their interplay with one another would be addressed.
Formulated products would also investigate the impact of shelf life and
excipients. The following is a brief synopsis of the various foci of this
investigation:

• Methods for determining the stability of related compounds such as

diazepam, bromazepam, cefixime, cefazolin, simvastatin, and lovastatin were
validated according to the European Pharmacopeia (2007).
• HPLC analysis to identify and characterize contaminants in study medicines.
• Diazepam, bromazepam, cefixime, cefazolin, simvastatin, and lovastatin:
third-party impurity analysis
• .Impurity analysis of finished drug goods from many manufacturers who
made the same medications.
• Stress-condition analysis of drug compounds for the detection of
contaminants.
• Correlation of impurities of drug substances and formulated products

Literature Review

Sources of Impurities

Impurities in drug substances may include the impurity present in the starting
material or the intermediates and bye-products formed during synthesis which
may be brought into the API as impurities or become a source of other
impurities resulting from them. The impurities related to the inert ingredients
(excipients) and solvents used during the synthesis may also become a
source of impurities in the API. Impurities in the drug products can be
introduced from the drug substances or from the excipients used for
formulating a drug product or can be brought into the drug product through
the formulation process or by contact with the packaging [15]. A number of
impurities can produce during storage (shelf life) or shipment of drug
products. It is essential to carry out stability studies to predict, evaluate and
ensure drug product safety [2].

Impurities in Selected Drugs

Degradation impurities in drugs are always the result of different degradation

reactions depending upon the chemical nature of drugs. Hydrolysis, oxidation and
photolysis are the most frequently occurring degradation reactions of drug substances
678

[16]. In this study Diazepam, Bromazepam, Cefixime, Cefazolin, Simvastatin, and

Lovastatin were selected to evaluate their impurities on the basis of their similar
degradation mechanisms, i.e., oxidationand hydrolysis[17-34].

Bromazepam and Diazepam

These belong to a class of drugs known as 1,4-benzodiazepines and are widely used as
minor tranquilizers, sleep inducers, sedatives and muscle relaxants [35-37]. The
drugs may also be used as antitumor antibiotics, antithrombotics and antipsychotics
[38]. Recent studies on diazepam have shown that it also inhibits shock induced
ultrasonic vocalization in adult rats [39]. Benzodiazepines are usually given orally
and are well absorbed by this route. Since the benzodiazepines are weak bases, they are
less ionized in the relatively alkaline environment of the small intestine and,
therefore, most of their absorption takes place at this site [40]. The presence of the
pyridine moity in the molecule is responsible for their unique physicochemical
properties. Their main metabolic routeinvolveshydroxylationand hydrolysis[41].

Cefixime and Cefazolin

Cefixime and Cefazolin, represent the cephalosporin group of β-lactam semi-

synthetic antibiotics derived from products of various microorganisms, including
Acephalopodia and Streptomyces. All cephalosporins have a 7-
aminocephalosporanic acid composed of ring fused to a β -lactam ring. Like
penicillins, they act by inhibiting synthesis of the bacterial cell wall [42]. β-lactam
ring is the chemical group associated with antibacterial activity. The different
pharmacological, pharmacokinetic, and antibacterial properties of individual
cephalosporins result from substitution of various groups on the basic molecule.
Cephalosporins also vary in acid stability and β-lactamas susceptibility [40].
These drugs are among the widely prescribed antibiotics for the treatment of
various infectious diseases [43].

Simvastatin and Lovastatin

Simvastatin and lovastatin are 3-hydroxy-3-methylglutaryl coencime A (HMG-

CoA) reductase inhibitors used in the treatment of hypercholesterolemia. HMG-
CoA reductase is a key enzyme in the biosynthesis of cholesterol. Statins are the
most often prescribed substances for reducing mortality related to coronary heart
diseases [44-48]. Simvastatin is absorbed from the GIT and is hydrolyzed to its
active β-hydroxy acid form. Simvastatin is a substrate for the cytochrome P-450
isenzyme CYP3 A4 and undergoes extensive first pass metabolism in the liver,
and mainly extreted in the faeces via the bile as metabolites [42]. Due to common
use, variable synthetic routes and availability in multiple dosage forms it is
important to work on the impurities associated with these drugs and to deal with
the determination of major degradation impurities using validated HPLC stability
indicating methods. The interrelationship between the various degradation
impurities and the role of the excipients on the degradation impurities of the
compounds in the drug products needs to be explored. Correlation of the
degradation impurities on aging is also required. Effect of stress conditions on the
reactions like hydrolysis and oxidation could be considerable in terms of the
degradation products [49].
 679

Physicochemical Properties of Selected Drugs

The physicochemical properties of some selected drugs are presented in Table 3a

–3c [50-52]. Pharmacological and Toxicological Data on Selected Drugs

Table 3
Physicochemical properties of diazepam and bromazepam Excremental Work

Physicochemical Compounds
Properties Diazepam Bromazepam
Appearance A white or White or
yellowish yellowish
Crystallinepowder crystallinepowder
Solubility Slightly soluble in water, Practically insoluble in
soluble in 1 in 25 of water, sparingly soluble
ethanol in alcohol and in
dichloromethane
Molecular formula C16H13C1N2O C14H10BrN3O
Molecular weight 284.75 316.2
pK avalue 3.33(200) 2.9,11.0.
Meltingrange 131-1350C 237o to 238.5o
with
decomposition.

Materials and Equipment

• Medicinal materials suspected of containing scum

• Microscope with a magnification of at least 400x
• Glass slides
• Coverslips
• Microscope slide staining kit (optional)
• Distilled water
• Fine-tip forceps or tweezers
• Scissors
• Scalpel or razor blade
• Sterile gloves
• Safety goggles

Procedure

• Put on sterile gloves and safety goggles to protect yourself from any
potential hazards.
• Obtain a small piece of the medicinal material suspected of containing
scums.
• Use scissors or a scalpel to cut the material into smaller pieces, no more
than 1 cm in size.
• Place a small piece of the material on a clean glass slide.
• Add a drop of distilled water to the material on the slide.
680

• Carefully place a cover slip over the material and gently press down to
flatten it.
• Place the slide under a microscope with a magnification of at least 400x.
• Observe the material under the microscope, looking for any visible scums or
other foreign materials.

Results and Discussion

HPLC methods validation

Degradation impurities of the chosen pharmaceuticals have been quantified using

a variety of spectroscopic and chromatographic techniques [31,50,80-94]. Most of
these strategies are based on the principle of induced breakdown of parent
molecules. The procedures for determining stability indicators in the
pharmaceuticals of choice here were taken from the European Pharmacopoeia
2009 [51] and applied to related chemicals (degradation impurities) of the drugs of
choice. Before applying a pharmacopeia approach to a specific drug, it must be
validated [11]. Parameters including as specificity, linearity, precision, and
accuracy (ICH) were used in the present work to partially validate the EP 2009
techniques for both the parent medicines and their common degrading
contaminants. The following is a discussion of the many factors that go into the
validation process:

Specificity

In the presence of possible contaminants and the formulation adjuvants, the

method's specificity is determined by its ability to assess the analyte reaction.
Various degradation impurities and formulation adjuvants from various
manufacturers were used to test the method's specificity for parent chemicals
(reference standards). The HPLC method was used to analyze the parent
substance, the principal degradation impurities, and the formulation adjuvants
using individual reference standards dissolved in the mobile phase. Parent
chemical, reference standard, formulation adjuvant, and impurity standards were
dissolved and analyzed in duplicate. There was no interference between the
various constituents, and all traces of the various components could be clearly
distinguished.

Linearity

The method's linearity was established through the development of calibration

curves for the parent compound and the principal degradation impurities. Test
solutions for linearity were made by diluting stock solutions of the parent
compound and degrading impurities by a factor of 50-150%. By comparing the
peak area of the parent component or impurity to its corresponding
concentration, calibration curves were generated. Over the concentration range
investigated, linear calibration curves were obtained for both the main compound
and each impurity.
 681

Precision

By injecting six replicas of the parent compound sample spiked with the known
concentration of each impurity, we were able to verify the method's accuracy.
Good precision was shown by a 3% RSD for both the original chemical and each
impurity.

Accuracy

To test how well this approach can quantify parent chemicals and related
contaminants in manufactured goods, we ran a series of standard addition and
recovery tests. Each degradation impurity was tested at three different
concentrations: 50%, 100%, and 150% of the parent chemical or impurity. Since
the overall mean of the recovery is between 97-103%, the accuracy of the method
is satisfactory for both the parent chemical and its primary degrading impurities
within the range of 50-150% of the prescribed level.

Table 1
Linearity data of bromazepam and its major impurities (n = 3)

Compound Slope Y-intercept Correlation

Coefficient
Bromazepam 0.76355 0.00217 0.9998

ImpurityA 3.33758 -0.0599 0.99989

ImpurityD 5.5976 0.00925 0.9998

This table provides the linearity data for Bromazepam and its major impurities,
based on three measurements. The data shows that Bromazepam has a slope of
0.76355 and a y-intercept of 0.00217, with a correlation coefficient of 0.9998.
Impurity A has a slope of 3.33758 and a y-intercept of -0.0599, with a correlation
coefficient of 0.99989. Impurity D has a slope of 5.5976 and a y-intercept of
0.00925, with a correlation coefficient of 0.9998. These correlation coefficients
indicate a strong linear relationship between the analyte concentration and the
detector response, with a high degree of accuracy. The linearity data in this table
suggests that the analytical method used to measure Bromazepam and its major
impurities is precise and reliable, with high percentages of correlation coefficients
ranging from 99.98% to 99.99%

Table 2
Recoveries of bromazepam from spiked samples

%Nominalcontent Amount added(µg) Amount found (µg) %Recovery

50 101.7 101.2 99.51
50 100.4 99.91 99.61
50 100.3 100.5 100.17
Mean: 99.77
100 200.4 199.7 99.64
100 200.3 201.1 100.28
 682

100 200.1 200.4 100.24

Mean: 100.05
150 302.2 300.76 99.87
150 300.6 301.1 100.07
150 300.3 300.1 99.87
Mean: 99.92

This table presents the recoveries of Bromazepam from spiked samples at

different concentrations, expressed as a percentage of nominal content. In each
row, the first column indicates the percentage of nominal content, and the second
column indicates the amount of Bromazepam added in micrograms (µg). The third
column shows the amount of Bromazepam found in micrograms (µg), and the
fourth column indicates the percentage of recovery. The results show that for
samples spiked with 50% nominal content, the mean recovery was 99.77%. For
samples spiked with 100% nominal content, the mean recovery was 100.05%,
and for samples spiked with 150% nominal content, the mean recovery was
99.92%. These percentages indicate the accuracy of the analytical method used to
measure the amount of Bromazepam in the spiked samples. A percentage of
recovery close to 100% indicates that the analytical method is precise and
reliable. Overall, the data in this table suggests that the analytical method used to
determine the recovery of Bromazepam is accurate and reliable, with mean
recovery percentages ranging from 99.77% to 100.05%.

Table 3
Repeatability results of bromazepam and ts major degradation impurities

SampleNo. %Bromazepam %ImpurityA %ImpurityC

1 101.1 100.3 98.5
2 100.2 102.5 98.71
3 99.2 99.2 102.5
4 100.5 98.2 98.71
5 99.6 100.4 102.1
6 100.10 99.3 100.7
%Mean 99.96 100.0 100.3
%RSD 0.763 1061 1.796

Table 3 shows the repeatability results of Bromazepam and its major degradation
impurities. The table lists six sample numbers, and the percentages of
Bromazepam and its major impurities A and C in each sample. The table also
shows the % mean and % RSD values. The % mean indicates the average
percentage of each component in the samples, and the % RSD indicates the
relative standard deviation of the results. The % mean values indicate that the
average percentage of Bromazepam in the samples was 99.96%, the average
percentage of Impurity A was 100.0%, and the average percentage of Impurity C
was 100.3%. These values suggest that the analytical method used to measure
the components in the samples was consistent and reliable.

The % RSD values indicate the degree of variation among the six samples. The %
RSD value for Bromazepam was 0.763%, which indicates low variability. However,
the % RSD values for Impurity A and Impurity C were 1061% and 1.796%,
 683

respectively, indicating a high degree of variability in the measurements of these

impurities. This high variability may suggest that the analytical method used to
measure these impurities needs to be improved. Overall, the data in this table
suggests that the analytical method used to measure the repeatability of
Bromazepam is reliable, as indicated by the low % RSD value. However, the high
% RSD values for Impurity A and C indicate that the measurement of these
impurities may be less reliable, and further optimization of the analytical method
may be need

Table 4
Linearity data of diazepam and its major impurities (n = 3)

Compound Slope Y-intercept Correlation

Coefficient
Diazepam 0.4366 -0.0135 0.9997
ImpurityA 0.8343 -0.0323 0.9996
ImpurityB 5.28257 -0.02224 0.9997

Table 4 shows the linearity data for diazepam and its major impurities. The table
lists three components, including diazepam and two impurities (A and B). For
each component, the table provides the slope, y-intercept, and correlation
coefficient values. These values can help to determine the linearity of the
analytical method used to measure these components. The slope value indicates
the relationship between the concentration of the component and the response of
the analytical method. The y-intercept value indicates the response of the
analytical method when the concentration of the component is zero. The
correlation coefficient value indicates the strength of the relationship between the
concentration of the component and the response of the analytical method.

The correlation coefficient values for all components were high, ranging from
0.9996 to 0.9997, indicating a strong linear relationship between the
concentration of each component and the response of the analytical method. The
slope values for diazepam and impurity B were similar, indicating that the
analytical method had similar sensitivity for these two components. However, the
slope value for impurity A was much smaller than for the other two components,
indicating that the analytical method may have lower sensitivity for measuring
this impurity. Overall, the data in this table suggests that the analytical method
used to measure the linearity of diazepam and its major impurities is reliable, as
indicated by the high correlation coefficient values. However, the difference in
sensitivity between the components suggests that the analytical method may need
to be optimized for measuring impurity A

Table 5
Recoveries of diazepam from spiked samples

%Nominalcontent Amount added(µg) Amount found (µg) %Recovery

50 99.51 100.22 100.71
50 101.3 101.62 100.38
50 100.2 100.53 100.38
Mean: 100.48
684

100 200.0 200.83 100.41

100 201.3 201.02 99.91
100 200.5 199.91 99.66
Mean: 99.97
150 299.51 300.01 100.17
150 302.41 302.11 99.91
150 300.71 301.21 100.15
Mean: 100.06

Table 5 shows the recoveries of diazepam from spiked samples. Three different
nominal contents (50%, 100%, and 150%) were analyzed, and for each nominal
content, three samples were tested. The amount added, amount found, and
percentage recovery were recorded for each sample. The mean percentage
recoveries were calculated for each nominal content, which were 100.48%,
99.97%, and 100.06% for 50%, 100%, and 150% nominal contents, respectively.
Overall, the results indicate good recoveries of diazepam from the spiked samples.

Table 6
Repeatability results of diazepam and its major degradation impurities

SampleNo. %Diazepam %ImpurityC %ImpurityD

1 100.2 102.2 99.7
2 100.5 101.5 100.71
3 101.2 100.4 98.5
4 99.5 99.2 102.4
5 100.00 99.8 101.8
6 101.4 100.3 101.2
%Mean 100.52 100.64 100.92
%RSD 0.698 1.147 1.454

Table 6 shows the repeatability results of diazepam and its major degradation
impurities. Six samples were analyzed, and the percentage of diazepam and its
two impurities (C and D) were recorded. The mean percentage of diazepam was
found to be 100.52%, while the mean percentage of impurities C and D were
100.64% and 100.92%, respectively. The %RSD (relative standard deviation)
values were calculated to determine the precision of the results. The %RSD for
diazepam was 0.698%, which indicates good precision. The %RSD for impurities
C and D were 1.147% and 1.454%, respectively, which are also within acceptable
limits. Overall, the results suggest that the method used for the analysis of
diazepam and its impurities is precise and reliable.

No Compound Retention Time (min)

1 Bromazepam 5.21
Impurity A 7.75
Impurity C 8.28
2 Diazepam 9.21
Impurity C 14.2
Impurity D 20.56
3 Cefiximetrihydrate 7.22
 685

Impurity A 6.21
Impurity E 3.63
4 Cefazolin Sodium 6.41
Impurity A 4.12
Impurity E 2.21
5 Simvastatin 2.72
Impurity A 1.22
Impurity C 6.51
6 Lovastatin 4.71
Impurity B 7.15
Impurity C 8.82

Determination of Impurities in Selected Drugs

The following sections detail the amount of active ingredients and key degrading
impurities found in various medicines. These numbers would reveal the extent of
contamination in samples from diverse origins. It is necessary to assess the
presence of contaminants when they are identified in concentrations higher than
those allowed by ICH guidelines (> 0.1%). Synthetic methods, shipping, bad
storage, and other factors can all contribute to medication degrading impurity.
The drug's efficacy, safety, and utility in compounded goods could be
compromised by the presence of certain contaminants. The quality of the raw
material and the final formulated products might be negatively impacted when
the producer does not always disclose the nature and concentration of undesired
contaminants contained in their products. By analyzing the drug's degradation
impurities, the producer can learn how to optimize its synthetic methods and
storage settings to reduce the amount of these contaminants, increase the drug's
stability over time, and guarantee the quality of the finished product. The next
sections contain assay results for samples that were kept in their original
packaging and kept at room temperature (25 1 0C) for a full year after their date
of manufacture.

The Origins, Distribution, and Impact of Contaminants in Active Pharmaceutical

Ingredients and Finished Pharmaceuticals. Many factors, including as the
synthesis procedure, the method of formulation, the nature of the excipients, the
probability of interaction, storage circumstances, packaging integrity,
transportation conditions, etc., contribute to the existence of impurities in
pharmacological substances and formed products. A drug's vulnerability to
environmental factors, excipient interactions, package contents, and so on can all
contribute to the presence of contaminants.

Overdosing on one contaminant can cause a cascade effect, wherein more, similar
impurities are produced in the dose form. Water, which can cause hydrolysis of
the medicine, and air, which can cause oxidation of the drug, are the most
common reactive species. Metal contaminants may hasten the breakdown of a
pharmaceutical compound. The drug's photosensitivity increases the risk of
radical generation and degradation in several contexts. Predicting the stability
properties of a pharmacological material through reformulation research can help
the formulator select the most stable formulation and storage conditions. The
contaminants introduced during degradation may be similar to those introduced
686

during the manufacturing process. One possible foundation for the management
of such contaminants is knowledge of their degradation mechanisms.

To ensure the product's continued quality and effectiveness, pharmacopoeias

often establish maximum allowable levels for any process impurities or degrading
impurities. Maintaining a product's desired qualities over the course of its usual
shelf life may be possible by the careful management of moisture content, solvent
residues, aerobic environment, and formulation factors in solid dosage forms.
Making a salt or appropriate derivative of a pharmacological ingredient can
reduce its chemical reactivity, and it may still be bioavailable. To ensure the
control of degradation impurities, suitable stability-indicating test techniques
must be provided for detecting and determining the parent chemical and the
degradation products. In order to determine the levels of degrading impurities in a
medicine, the pharmacist may need to create stability-indicating procedures. To
detect, identify, and quantify trace contaminants in medicinal ingredients and
manufactured products, highly sensitive analytical techniques such as gas
chromatography–mass spectrometry, high performance liquid chromatography–
mass spectrometry, radioimmunoassay, fluorometric measures, atomic
absorption, and spectroscopy are available.

The purification process for the drug ingredient can be carried out meticulously to
get the item in its purest form possible by removing any solvent residues,
unwanted moisture, and associated contaminants. If these substances were
absent, any potential interactions that could lead to a degrading impurity would
not take place. Maintaining a verified process and adhering to good
manufacturing procedures would guarantee that the hypothesized contaminants
would not make it into the final product. Regulations [15] and concerns about
quality and safety suggest that frequent determination of significant
contaminants may be necessary. It is difficult to devise an effective impurity
control approach without first understanding the stability of pharmaceuticals and
formulated goods and the pathways by which they degrade. Many authors
[53,96,100-103] supply such details for the formulator's convenience.

Conclusions

Loss of activity, effectiveness, and safety can result from the presence of
contaminants in pharmacological ingredients and finished products. Guidelines
for limiting the presence of contaminants in pharmaceutical ingredients have
been established by official compendia and regulatory bodies. Bromazepam,
diazepam, Cefixime trihydarte, cefazolin sodioum, simvastatin, and lovastatin, as
well as their formed products, were analyzed in this work to characterize and
evaluate key degradation impurities. The study's major findings can be summed
up as follows:

Characterization of Parent Drugs and Degradation Impurities

The parent medicines and their degrading impurities were characterized in this
investigation using high-performance liquid chromatography. Separation between
a drug and its impurities is excellent, with tR values for both the parent
pharmaceuticals and the degradation impurities falling within 20 minutes of one
 687

another. The impurities were characterized by comparing their tR values to those

of standard reference materials.

Assay of Parent Drugs and Degradation Impurities

The specificity, linearity, accuracy, and precision of the HPLC techniques from the
European Pharmacopoeia for the individual pharmaceuticals have been verified
and applied to the assessment of these compounds and the corresponding
degrading impurities. Impurity concentrations in the percent range over the
reporting limitations of ICH and other regulatory organizations need
consideration. Overall, the test method was determined to have an RSD of 3% or
below. There is no interference in the assay of either compound from the parent
chemicals or the degradation impurities.

Correlation of Degradation Impurities in Drug Substances and Formulated

Products

Each drug substance was tested for two primary degrading impurities in this
investigation. Different manufacturers' finished products and the raw materials
used to make them have varying amounts of these contaminants. Different
environmental elements, drug-excipient interactions, drug-impurity interactions,
or differences in the synthesis processes itself could all have a role.

Forced degradation of selected Drug Substances

Some medications have been subjected to H2O2 and 80 degrees Celsius to speed
up their breakdown in an acidic or alkaline medium. This has led to significant
degradation and suggests the production of potentially detrimental contaminants
during extended storage or under bad storage circumstances. Hydrolytic
processes are the primary pathway for the breakdown of these medicines, but
oxidative degradation may also occur.

Effect of Degradation Impurities on Formulated Products

If there is an excessive amount of degrading contaminants in a formulation, the

quality, efficacy, and safety of the product may decline. It is advised that the
formulator consider all of the factors that contribute to the formation of
degradation impurities of a certain medicine, and then employ a formulation
approach to minimize the formation of such impurities within the drug's typical
shelf life. Development of a product's formulation can benefit from previous
formulation research conducted on the pure drug ingredient, which can shed light
on the substance's stability qualities and degradation procedure.

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