INTRODUCTION:

Drug compounding is still carried out throughout the world, especially in developing countries like Indonesia. It provides patient’s needs who cannot swallow solid dosage forms such as tablets or capsules or for individualized doses that are not available on products on the market. However, the quality and the safety of compounded drug cannot be guaranteed¹. The compounding process has not been validated, the equipment has not been calibrated, raw materials are not standardised, personnels are not trained/do not have enough knowledge, and laboratory tests are not carried out to verify the potential, purity, and quality of medicine². All of this factor could result in medication errors.

Drug compounding can be at risk of causing medication errors, either due to calculation errors, compounding process errors, or the quality of preparations that do not meet standards³. Besides, incompatibility might occur in the compounding product. In the study by Monajjemzadeh et al., (2009) there is a chemical incompatibility in the mixture of acyclovir and lactose, which is the presence of a Maillard reaction⁴. In the mixture of aspirin and phenylephrine hydrochloride, there is a chemical incompatibility, namely the occurrence of the transaceration reaction in the mixture which produces n-acetyl-phenylephrine compounds and salicylic acid⁵. The risks of drug compounding are the unproven quality, stability, safety, and efficacy of the product, compared with what the manufacturers do.

The pharmacist has a responsibility to give medicine with good quality, safety, and efficacy⁶. Pharmacists might do extemporaneous compounding of finished products into a new dosage form that is different from the original dosage form. The alterations in a dosage form can change the quality, safety and efficacy of the drug⁷. For example, the risks might occur when a drug from the manufacturer was crushed to make a new dosage form, such as drug instability, changing of the pharmacokinetic profile, and drug irritation⁸. It happened in a combination of vitamin B complex tablet and tablet containing Pseudoephedrine Hydrochloride and Chlorpheniramine Maleate, which experienced physical instability⁹. Therefore, a pharmacist must be able to understand the physical and chemical properties of drug ingredients before being mixed to ensure that the drugs formulated do not experience incompatibility and instability⁶.

The problem was there was a limited study about instability and incompatibility of compounded drug/extemporaneous preparation. This study’s aim was to provide an overview of compounding practice in divided powder preparation in Indonesia as a developing country and as a case study of potential incompatibility and instability of an extemporaneous preparation. In the end, this study might consider pharmacist when compounding a divided powder.

MATERIAL AND METHODS:

This research is non-experimental research and observational descriptive. The sampling method is purposive sampling. Data collection was conducted prospectively in a private hospital in Indonesia.

RESEARCH OBJECTIVES:

The object for this research was prescriptions that meet the following inclusion criteria:

a. The prescription is written in the five months of study (January to May 2019).

b. The prescription was written by general practitioners or specialist doctors at the hospital where the research was conducted.

c. The prescription contains an order to compound drug.

All recipes that meet the inclusion criteria were then recorded and grouped based on the active substances contained, and afterwards the frequency of appearance of these recipes were counted. The most frequently prescribed formula was used for the case study. The case study was restricted to technical risk analysis and analysis of potential incompatibility and instability.

Technical risk assessment:

Risk assessments tool that was designed and developed by senior pharmacists at Leeds Teaching Hospitals NHS Trust and the University of Bradford UK for extemporaneous preparation was adopted on this study (Handbook of Extemporaneous Preparation)¹⁰, as follows in table I.

Tabel I. Technical risk assessment based on Handbook of Extemporaneous Preparation¹⁰

The complexity of calculation

The complexity of the compounding process

Low

Medium

High

Simple

Box A

(score 2)

Box B

(score 4)

Box C

(score 6)

Medium

Box D

(score 4)

Box E

(score 6)

Box F

(score 8)

Complex

Box G

(score 6)

Box H

(score 8)

Box I

(score 10)

Justification for the complexity of calculations

- Simple: without calculation, calculation with simple addition, subtraction, division and multiplication

- Medium: calculation involving unit changes but still in the same unit (example mg to g)

- Complex: calculation involving changes in units of different units (units of volume to weights), dilution

Justification for the complexity of the compounding process

- - Low: involves <3 compounding stages

- - Medium: involves 4-5 compounding stages

- - Height: involves > 6 stages of compounding, or compounding using a special tool (tablet crusher, blender, homogeniser)

Analysis of potential incompatibility and instability

Analysis of potential incompatibility and instability was done by literature review. The inclusion criteria for information of literature were taken from:

1. A compendium (Indonesian Pharmacopoeia, United State Pharmacopeia, British Pharmacopeia, Japan Pharmacopeia),

2. Drug databases (drugbank.ca and pubchem.ncbi.nlm.nih.gov),

3. Documents or articles from official sites (Indonesian National Agency of Drug and Food Control, Indonesian Health Ministry, Food and Drug Administration, World Health Organization), and

4. Scientific journal.

Document or articles from official sites were searched in each official website. While the scientific article search was carried out systematically using the search engine such as Google Scholar and PubMed with the minimum year limit of articles is set to a 2008 issue. If there was no information collected from the year limit setting, then the setting was removed. Keywords used for the search were the names of each drug, stability of (drug name), incompatibility of (name of drug or group of drugs), drug interaction / pharmaceutical drug interaction of (name of drug), and degradation of (name of drug or group of drugs). The search was conducted in Indonesian and English.

RESULT:

Six hundred sixty-six prescriptions were containing an order to compound drug into divided powder. The five most prescribed formula and the result of technical risk assessment were shown in Table 2.

Table II. Five formulas with the highest frequency

No	Formula	Frequency	Technical risk score
1	Ketotifen ½ tab Cyproheptadine ¼ tablet Cetirizine ½ tablet	112	6 (Box C)
2	Ketotifen ½ tab Cyproheptadine ¼ tablet	87	6 (Box C)
3	Acetaminophen 1/5 tablet	34	4 (Box B)
4	Albuterol 1/3 tab	30	4 (Box B)
5	Triamcinolone 2 mg Lactose pulvis Carmine	28	6 (Box C)

The literature research for analysis of potential incompatibility and instability was started by compiling physical and chemical properties of the drug (in Table II.). The result was shown in Table III.

Table III. Physicochemical properties of ketotifen fumarate, cetirizine hydrochloride, and cyproheptadine hydrochloride

Drug	Ketotifen Fumarate	Cetirizine Hydrochloride	Cyproheptadine Hydrochloride	Acetaminophen	Salbutamol sulfate	Triamcinolone
Chemical formula	C₂₃H₂₃NO₅S^11–13	C₂₁H₂₇Cl₃N₂O₃ ^13–15	C₂₁H₂₂ClN ^13,16,17	C₈H₉NO₂^18,19	C₂₆H₄₄N₂O₁₀S ^20,21	C21H27FO6 ^22,23
Molecular weight	425,5 g / mol ^11–13	461,8 g/mol ^13–15	323,859 g / mol ^13,16,17	151,16 g / mol ^18,19	576,7 g/mol ^20,21	394,4 g/mol ^22,23
Organoleptic	White to yellowish crystalline powder and odourless ¹³	White crystalline powder ¹³	White to slightly yellow powder and odourless or practically odourless ¹³	White crystal powder, odourless, slightly bitter taste ¹³	White crystalline powder ²⁴	White crystalline powder, white or practically white, and odourless ¹³
Solubility	Slightly soluble in water ¹³	Very soluble in water ¹³	Difficult to dissolve in water ¹³	Easily soluble in alcohol, soluble in boiling water and 1N NaOH ¹³	Slightly soluble in water, soluble in ethanol 96% ²⁴	Very difficult to dissolve in water, in chloroform, and ether, ethanol and methanol ¹³
Melting point	192^oc ^11,12	110^oc ^14,15	112.3-113.3 °C ^16,17	169-170 °C ¹⁸	180°C^20,21	269-271 °C ^22,23
Log P	3,49 ^11,12	2,98 ^14,15	5,02 ¹³	0,46 ¹⁸	0.44 ²⁰	4,69 ^22,23
Hygroscopicity	In salt form, might be hygroscopic²⁵	In salt form, might hygroscopic²⁵	In salt form, might hygroscopic ²⁵	No	In salt form, might hygroscopic ²⁵	No
Stability to light	Ketotifen fumarate was stable against photodegradation²⁶	Cetirizine hydrochloride might experience photolysis with infrared light (8% in 24 hours), ultraviolet light (9% in 24 hours), and shed sunlight (10% in 15 days) ²⁷	Stable against photodegradation including sun exposure ^26,28	Paracetamol exposed to sunlight for 120 minutes experienced degradation of 4.52% ²⁹	Salbutamol exposed to sunlight for 48 hours experienced 9.567% degradation ³⁰	Triamcinolone exposed to sunlight for 12 hours can be degraded by 33.87% ³¹
Stability against humidity	Ketotifen fumarate was stable against humidity ²⁶	Cetirizine hydrochloride has excellent stability after stored at 45-50^o C in 75% RH for six months ^27,32	Cyproheptadine hydrochloride tablet was stable at RH 40^oc ± 20^oc in 75 ± 5% RH for one month ³³	Paracetamol is relatively stable with humidity for seven days ³⁴.	Salbutamol dissolved in 80° C hot water for 2 hours experienced degradation of 9,364%. ³⁰	Triamcinolone dissolved in water 80^oC for 8 hours was experienced degradation of 4,27% ³¹.
Stability against high temperature	Ketotifen solution (in 0,1% tween 80 formulations) was degraded more than 90% when treated in 50^oc ³⁵	Cetirizine hydrochloride has a good stability n 105^oc in dry condition ^27,32	Cyproheptadine hydrochloride potential degradation in high temperature ³⁶	Paracetamol exposed to heat at 105 ° C for 30 minutes experienced degradation of 15.95% ²⁹	Salbutamol exposed to heat at 70 ° C for 48 hours experienced degradation of 3.174%. ³⁰	Triamcinolone has a good stability against temperature 80^oc ³⁷
Stability against oxidising agents	Ketotifen Fumarate is compatible with strong oxidising agents and strong acids.	Cetirizine hydrochloride might be oxidated due to the presence of oxidating agent ³⁸	Cyproheptadine hydrochloride was degraded by increasing oxidising agent ³⁶	Paracetamol which was exposed to 6% hydrogen peroxide for 60 minutes experienced degradation of 24.10% ³⁴.	Salbutamol exposed to 30% hydrogen peroxide at 80 ° C for 2 hours experienced 11.52% degradation ³⁰	Triamcinolone reacted with 6% hydrogen peroxide for 6 hours at 40^oc experienced degradation of 13.90% ³¹
Another stability aspect	Ketotifen fumarate experiences protonation at a ph below two and deprotonation at ph above 6 or 7 ³⁹	Cetirizine hydrochloride is incompatible with excipient polyethyleneglycol and another oxidating agent ³⁸	Cyproheptadine hydrochloride oxidated a ph below 2.8, produce cyproheptadine N-Oxide ^36,40	Paracetamol was experience degradation with strong acid and strong base for 60 minutes ³⁴.	Salbutamol which was exposed to 0.1M HCL and 0,1 M NaOH at 80 ° C for 2 hours experienced degradation of 6.12% and 10,6% ³⁰	Pure triamcinolone which was exposed to strong acid (0.1 N HCl) for 6 hours and bases (0.1 NaOH) for 90 minutes at 40^oc would be degraded 13.06% and 97.69% ³⁷

DISCUSSION:

The prevalence of compounding drug preparation into divided powder in the centre study was quite often. It was also found that although a drug was available in dosage forms for pediatric, it was still compounded. For instance, acetaminophen was available in liquid oral or liquid drop dosage form for pediatric. However, in this study, we found that acetaminophen was crushed and compounded into divided powder. After confirmation to the pharmacist, it was clear that most of the patient in the centre study had a belief that pulverised drug/divided powder is more effective than other dosage forms. This phenomenon could indicate that most of the patients have profound knowledge about dosage form and its effect.

The first and second most frequently prescribed prescriptions were written for patients with a diagnosis of allergic rhinitis by pediatricians. Its combination can reduce allergy, and cyproheptadine can increase appetite based on off label use⁴¹. The third prescription was indicated for antipyretic and analgesic¹⁸. The forth was for asthma²¹, and the last was as a corticosteroid²².

The first formula as the most frequently prescribed initiates the pharmacy department to make preparations of small-scale for the hospital's needs (stock). The divided powder containing a combination of ketotifen tablet, cyproheptadine tablet, and cetirizine tablet was produced using tablet crusher all at once. The powder was white and odourless. However, the powder also shows agglomerate or possibly a coarse powder because the crushing process was not adequate. The powder was packaged in a tightly closed paper bag. The secondary package of the powder in storage at the pharmacy department is in a tightly closed container. Beyond use date for the powder was calculated using the formula based on USP <795>.

Figure 1. Equipment for compounding: (a) tablet crusher, (b) powder divider board, (c) powder paper bag, and (d) sealer

Other formulas which were being compounded in small scale production were formula 2 and formula 5. Generally, the procedure to compound divided powder in small scale production in the centre study was as follow:

1. Calculating the materials

2. Putting all of the materials into the tablet crusher (Figure 1a)

3. Crushing and blending the mixture using tablet crusher

4. Taking out the powder

5. Dividing powder into powder divider board (Figure 1b)

6. Pouring powder from divider board into powder paper bag (Figure 1c)

7. Sealing the powder paper bag using sealer (Figure 1d)

8. Storing in tightly container

While the formula 3 and 4 were compounded instantaneously when the doctor prescribed it. Generally, the procedure to compound divided powder instantaneously in the centre study was as follow:

1. Calculating the materials

2. Putting all of the material into mortar

3. Crushing and blending the mixture in the mortar using a pestle

4. Taking out the powder

5. Dividing powder into powder divider board

6. Pouring powder from divider board into powder paper bag

7. Sealing the powder paper bag using a sealer

8. Storing in tightly container

Based on confirmation to the pharmacist, preparations of formulas 1 through 5 were using simple calculation principles. It was done by multiplying each portion of the tablet by the amount of powder to be made. The simple complexity of the calculations means this formula has a low risk of causing calculation errors. Although the calculation is simple, this process must be considered because after all, calculation errors are the most common thing in compounding errors and can be harmful to patients.

While based on the complexity of the compounding process, it was clear that the difference between small scale production for stock and instantaneously compound was the tools. Small scale production was using tablet crusher. It made the risk for compounding process higher¹⁰. Compounding with a tablet crusher involves heat, contact with a blade (a metal that can catalyse oxidation), and a high risk of cross-contamination due to the difficulty of cleaning the blender/tablet crusher. Moreover, pulverising using tablet crusher might cause drug loss⁴². Although compounding using a blender is time-efficient because the mixture is made in sufficient quantities for the stock in the hospital, on the other hand, it might decrease the drug stability if it is degraded by metal catalysis or by heat. This consideration could explain why formulas 1, 2 and 5 have higher technical risk values compared to formulas 3 and 4. So it can be concluded that the difference in mixing risk in the five formulas is only based on the complexity of the calculation. The technical risk analysis was essential to be done because general compounding errors were caused by such as calculation errors, improper use of equipment, lack education and training of pharmacist/technicians, misinterpretation order/formula instruction, and lack of focus. One of the ways that can be done for risk management in compounding is to do a risk assessment.

In addition to compounding technical risk analysis, pharmacists should understand the physical and chemical properties of the components of the drug. Understanding of the physical properties of drug molecules can support the identification of potential incompatibilities and instability in drug mixtures. The summary of the physical-chemical properties of the three drugs is in table III.

In the first formula, the compounding of cetirizine tablet, ketotifen tablet, and cyproheptadine tablet from the original dosage form into a divided powder might lead to instability, mainly because most of the drugs were available in its salt form which might show hygroscopic properties. In general, the three drugs are relatively stable. Compounding was done using a blender, and the rotation of the blade can produce heat. However, since the drugs are stable, the heat that might occur in the process will not affect instability. The compounding drug should be kept away from sunlight because cetirizine hydrochloride is photosensitive. The simple thing to prevent photolysis of cetirizine hydrochloride is to use light-resistant packaging. For powder, a pharmacist might use dark box/plastic as a secondary package to maintain stability. One potential incompatibility that can occur in all drugs is with oxidising agents. In this compounding process, the pharmacist did not add an oxidizing agent. So this potency expectantly does not occur. The following formula, compounding of ketotifen and cyproheptadine had a similar profile potency with the first formula, without considering adding cetirizine hydrochloride.

The third formula and fourth formulas were compounded only by changing the dosage form. Both were compounded individually without adding another component. There were not found any incompatibility potency in these formulas. Nevertheless, if possible, acetaminophen tablets and salbutamol tablets should not need to be made into divided powders. Both acetaminophen and salbutamol are available as syrup or pediatric preparations. If there were a commercial product that provides patient needs, compounding should be avoided¹⁰ to prevent compounding errors. The last formula contains triamcinolone tablet and lactose and carmine as an excipient. No incompatibility issue happened between all of the components. Furthermore, pharmacist still needs to consider about hygroscopicity of lactose. Carmine was needed as an indicator of homogeneity.

Most of the drugs compounded in the centre study were in salt form. The important thing that should be considered is that a drug in the salt form are hygroscopic²⁵, where the drugs were able to absorb and retain moisture at various temperatures and humidity. Since the drug was compounded into a powder, the surface area of the particle is wider. The wide surface area can affect moist absorption by the powder because of its hygroscopic properties. If the moisture content in powder is too high, it can affect its stability. Aesthetically, the appearance of the divided powder will worsen because the powder will agglomerate and therefore, decreases its homogeneity. Furthermore, high moisture content might cause microbial instability. To decrease the moisture adsorption, the pharmacist could use a tightly closed container and add an adsorbent, for instance a silica gel. The storage information for the patient should be clearly stated to store the drug in a dry place and kept from sun light. This action hopefully might maintain the drug stability up to beyond use date.

CONCLUDING:

Drug compounding practices in developing countries, especially in Indonesia, still exist. Case studies on the prescription of compounding divided powder in Indonesia show that five most frequently prescribed formulas have the potency to experience instability and incompatibility. The most of instability potency was caused by the hygroscopicity of the drugs in salt form. The other potency that might happen was degradation because the drugs were photosensitive. The simple solution to this problem is by giving the most appropriate packaging and storage instruction for the patient. Based on this study, we can suggest that a pharmacist must be able to understand the physical and chemical nature of each drug that is prescribed to determine the potential instability and incompatibility that may occur in a prescription or compounding order. Furthermore, the pharmacist can determine the most appropriate solution to overcome the incompatibility or instability that occur. This is the part of quality assurance of compounding preparations, so that patients will get safe and effective drugs, and can prevent medication errors.

ACKNOWLEDGEMENTS AND FUNDING:

The author(s) received funding from The Ministry of Research, Technology and Higher Education of The Republic of Indonesia with contract number DIPA-042.06.1.401516/2019.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 04.12.2019 Modified on 19.02.2020

Research J. Pharm. and Tech. 2020; 13(12):6231-6237.

DOI: 10.5958/0974-360X.2020.01086.0