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1 s2.0 S0928098717300490 Main PDF
1 s2.0 S0928098717300490 Main PDF
1 s2.0 S0928098717300490 Main PDF
Formulating a poorly water soluble drug into an oral solution suitable for
paediatric patients; lorazepam as a model drug
A.C. van der Vossen a,⁎, I. van der Velde a, O.S.N.M. Smeets b, D.J. Postma b, M. Eckhardt c, A. Vermes a,c,
B.C.P. Koch a,c, A.G. Vulto a, L.M. Hanff a
a
Department of Hospital Pharmacy, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
b
Royal Dutch Pharmacists Association (KNMP), PO Box 30460, 2500 GL Den Haag, The Netherlands
c
A15 Pharmacy, Buys Ballotstraat 2, 4207 HT Gorinchem, The Netherlands
a r t i c l e i n f o a b s t r a c t
Article history: Introduction: Many drugs are unavailable in suitable oral paediatric dosage forms, and pharmacists often have to
Received 16 November 2016 compound drugs to provide paediatric patients with an acceptable formulation in the right dose. Liquid formu-
Received in revised form 12 January 2017 lations offer the advantage of dosing flexibility and ease of administration to young patients, but drug substances
Accepted 22 January 2017 often show poor aqueous solubility. The objective of this work was to study different solvents and matrices to de-
Available online 23 January 2017
sign a liquid formulation for poorly water soluble drugs, using lorazepam as model drug.
Methods: Three different formulation strategies were explored to improve the solubility. Firstly, water-soluble or-
Keywords:
Lorazepam
ganic solvents were used to improve the aqueous solubility directly, secondly, ionic surfactants were used to sol-
Paediatrics ubilise the model drug, and thirdly, complexation of lorazepam with cyclodextrin was studied. Specific attention
Cyclodextrins was paid to excipients, adequate taste correction and palatability. For the final formulation, physical and chemical
Propylene glycol stability and microbiological quality were assessed for 12 months.
Oral solution Results: An organic solvent based formulation, containing a mixture of polyethylene glycol and glycerol 85%, with
HP-β-CD a minimum amount of propylene glycol, proved to be physically and chemically stable. Development of the non-
ionic surfactants formulation was discontinued due to taste problems. The cyclodextrin formulations were phys-
ically stable, but lorazepam content declined to 90% within five months. The final formulation contained in vol-
ume concentration (%v/v) 87% glycerol, 10% polyethylene glycol 400 and 3% propylene glycol. Orange essence
was the preferred taste corrector. The formulation remained stable for 12 months at 4 °C, with lorazepam content
remaining N 95%. Related substances increased during the study period but remained below 2%. In-use stability
was proven up to 4 weeks.
Conclusion: An organic solvent based oral formulation was shown to be superior to a non-ionic surfactant based
formulation or a cyclodextrin formulation. These results may help to formulate paediatric formulations of other
poorly water soluble drugs, to aid pharmacy compounding.
© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
http://dx.doi.org/10.1016/j.ejps.2017.01.025
0928-0987/© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
206 A.C. van der Vossen et al. / European Journal of Pharmaceutical Sciences 100 (2017) 205–210
administration, and generally solid formulations are more stable than Alternatively, a poor water-soluble drug can be solubilized using surfac-
liquid formulations. However, for most compounding pharmacies, tants, like polysorbate 20 and 80 (Tween) or polyoxyl hydrogenated
tableting is not an available technique. Liquid formulations are therefore castor oil (Cremophor), to obtain micelles in an aqueous environment.
still commonly applied by pharmacist that need to compound for paedi- Similarly, surfactants can be used to obtain a microemulsion, when
atric patients, both on individual and batch scale. combined with a polar solvent, an oil, and a cosurfactant. Lastly, com-
Drug substances sometimes show poor aqueous solubility. The use of plexation of poorly soluble drugs with cyclodextrins has been a strategy
solubilizing excipients can improve this, but especially in the paediatric to increase the aqueous solubility and bioavailability of compounds,
population, the use of excipients needs to be considered carefully, with re- while at the same time masking the taste (Committee for Human
spect to safety and palatability. The objective of this study was to explore Medicinal Products (CHMP), 2014a), an important aspect in the design
different formulation strategies for a poorly water soluble drug substance, of paediatric formulations.
lorazepam was chosen as a model drug. The objective of this study was to explore different formulation
Lorazepam (7-chloro-5-(2-chlorophenyl)-3-hydroxy-2,3-dihydro- strategies to process a poorly soluble drug substance into a clear oral so-
1H-1,4-benzodiazepin-2-one) is a benzodiazepine indicated for the lution, using lorazepam as a model drug. The formulation needed to be
treatment of generalized anxiety disorder and pre-surgical (Lexicomp suitable for paediatric patients from the age of one month, and have ad-
Online®, 2016). Off-label, it is applied in a wide range of indications equate stability to allow for individual and batch production within the
and patient categories, because of its sedative and anticonvulsive activ- pharmacy.
ity and absence of active metabolites. Within paediatrics, it is adminis-
tered to children from the age of one month for acute anxiety, 2. Material and methods
sedation, chemotherapy induced- or associated nausea, status epilepti-
cus or for weaning purposes (Lexicomp Online®, 2016). 2.1. Materials
Currently, no liquid dosage form of lorazepam is available in the EU.
An extemporaneous suspension of 1 mg/ml, prepared from 2 mg tablets, Lorazepam drug substance was bought from Fagron BV (Capelle
distilled water, Ora-Plus® and Ora-Sweet®, has been proven to be a/d IJssel, The Netherlands) and Duchefa Farma BV (Haarlem, The
chemically stable for up to three months when stored at 4 °C (Lee et Netherlands). Lorazepam related compound B and hydroxypropyl-
al., 2004). However, a subsequent study using this suspension proved β-cyclodextrin (HP-β-CD, substitution degree 0.6) were bought
that dosage measurement by paediatric intensive care nurses led to sig- from Sigma-Aldrich Chemie BV (Zwijndrecht, The Netherlands).
nificant deviations from the intended dose (Lee et al., 2005). These inac- Lorazepam related compounds C and D were bought from USP
curate dosage measurements are less likely to occur in the case of an Switzerland (Basel, Switzerland). Colour Reference Solutions Y
oral solution, but the physical and chemical characteristics of lorazepam were bought from Merck Millipore (Amsterdam, The Netherlands).
make this a challenge. Lorazepam drug substance and all other excipients were European
There are different strategies to formulate a poorly water soluble Pharmacopoeia grade.
drug substance into an oral solution. pH Adjustment can be used to ion-
ize a compound, which generally will result in increased aqueous solu- 2.2. Formulation development
bility. In the case of lorazepam (aqueous solubility 0.08 mg/ml) (O'Neil,
2006), with pKas of 1.3 and 11.5 (Clarke's Analysis of Drugs and Poisons The dosage strength was chosen based on the target population of
[Internet], 2016), pH adjustment is not a feasible method to increase the children from the age of one month to 18 years old, receiving a maxi-
solubility. It is also sensitive to hydrolysis in both acidic and basic envi- mum dose of 0.6 mg/kg/day (Lexicomp Online®, 2016). To limit the vol-
ronments (Siddegowda et al., 2012) and shows temperature-dependent ume needed and excipients administered, we aimed for a strength of
degradation (McMullan et al., 2013). Organic solvents can be used as an 1 mg/ml. Three different formulation strategies were explored to im-
alternative to water, but specific attention has to be paid to safety in prove the solubility. Firstly, water-soluble organic solvents were used
paediatric patients. A distinction can be made between water-soluble to improve the aqueous solubility directly, secondly, non-ionic surfac-
and water-insoluble organic solvents. Water-soluble co-solvents, like tants were used to solubilise the model drug, and thirdly, complexation
ethanol (lorazepam solubility 14 mg/ml) and propylene glycol (loraze- of lorazepam with cyclodextrin was studied. Parameters that were stud-
pam solubility 16 mg/ml) (O'Neil, 2006), create a mixed aqueous/ ied were; physical stability (by visual inspection), chemical stability,
organic solution. These excipients are readily available and easy to pro- using the analytical assay described in Section 2.5, and palatability
cess, but they can convey a risk of toxicity to children (Committee for (see Section 2.3). Physical instability was defined as the presence of vis-
Human Medicinal Products (CHMP), 2006). A combination of water- ible precipitation. The visual inspection of the samples was performed
insoluble organic solvents, such as medium-chain and long-chain tri- according to Ph. Eur. 2.2.1., with use of commercial reference solutions.
glycerides and oleic acid, can be used to disperse lipophilic drugs. The physical and chemical stability were initially studied for 5 months.
2.2.1. Organic solvents end, two batches of 3000 ml each were compounded, to investigate
For the organic solvents-based formulation, we experimented with the influence of temperature and packaging material on long term
different ratios of propylene glycol (PG), poly ethylene glycol 400 stability. The test formulations were prepared with active pharma-
(PEG400) and glycerol 85%. Efforts were directed towards a glycerol/ ceutical ingredient (API) from two different suppliers (Fabbrica
PEG400 based mixture containing minimal amounts of propylene glycol Italiana Sintetici S.p.A and Cambrex Profarmaco Milano S.r.l.). Sam-
(Fig. 1). ples were stored in climate cabinets at 4 °C (VTL650K, range 2–
8 °C) and 25 °C 60% relative humidity (Elbanon type LC 500, range
2.2.2. Non-ionic surfactants 23–27 °C, 55–65% RH) in amber-coloured polyethylene terephthal-
The second strategy that was explored was the use of non-ionic ate (PET) and glass containers. In each cabinet the temperature was
surfactants to create a micellar solution. Polysorbate 80 and sorbitan registered hourly. Because of the known temperature dependent
monooleate were mixed in a ratio to obtain a hydrophilic/lipophilic degradation of lorazepam, stability studies at 40 °C were omitted.
balance (HLB) of 11.5. The total surfactant content in the test formu- Samples were tested against the release or end-of-shelf life specifica-
lations ranged from 1 to 5%. PEG400 was used to dissolve lorazepam, tions, based on the United States Pharmacopeia (USP) monograph
after which the micellar solution was slowly added to the PEG400. for lorazepam oral concentrate and the general Ph. Eur. monograph
The volume per test formulation was 50 ml, the composition of the for microbiological quality of non-sterile pharmaceutical prepara-
excipients is displayed in Fig. 2. tions, shown in Table 1. Samples stored at 25 °C were analysed at 0,
1, 2, and 3 months. Samples stored at 4 °C were also analysed at 6,
2.2.3. Cyclodextrin 9 and 12 months.
For the cyclodextrin formulation, HP-β-CD was chosen as the
complexing agent, because of its high water solubility, lower cost com- 2.5. Analytical assay
pared to other cyclodextrins, low toxicity (Committee for Human
Medicinal Products (CHMP), 2014a), and based on previous work investi- For the quantitative analysis of lorazepam and lorazepam related
gating different cyclodextrins for inclusion complexation of lorazepam compounds (USP) B, C and D [2-amino-2,5″-dichlorobenzophenone, 6-
(Holvoet et al., 2005). A phase solubility diagram was made to measure chloro-4-(o-chlorophenyl)-2-quinazolinecarboxaldehyde and 6-chloro-
the solubility of lorazepam as a function of the HP-β-CD concentration. 4-(o-chlorophenyl)-2-quinazolinecarboxylic acid, respectively] a high
This revealed that a minimum of 54 mg/ml HP-β-CD was required to ob- performance liquid chromatography combined with UV (HPLC-UV) de-
tain a 1 mg/ml lorazepam solution after 4 h of ultrasonification. However, tection method was used. The components were separated using a
a HP-β-CD solution of 60 mg/ml (formulation C1) proved not sufficient to Shimadzu LC20 system, on a C18 analytical column (Inertsil ODS-3.5 μm
maintain a stable product after one week, therefor the HP-β-CD concen- 150 × 4.6 mm) with a mixture of acetonitrile, methanol and ammonium
tration was increased to 100 mg/ml (formulation C2). Glycerol 85% was acetate solution (100 mM, pH 6.0 ± 0.04 adjusted with 1 M acetic acid) in
added as a preservative in an amount of 35% m/v. the ratio 1:1:1 (v/v/v) as mobile phase, at a flow rate of 1.0 ml/min. Col-
umn temperature was kept at 30 ± 0.1 °C and UV detection for quantifi-
2.3. Palatability cation was performed at 230 nm using a Shimadzu M20A diode array
detector, while the wavelength range of 200–400 nm was continuously
The palatability of the test formulations was assessed by three monitored for unidentified peaks. The injection volume was 20 μl. The
adults, experienced in taste assessment. Characteristics that were eval- method was validated for the quantification of lorazepam in the cyclodex-
uated were smell, taste, aftertaste and mouthfeel, and they were inde- trin and PG/PEG 400/glycerol sample matrices and in the presence of re-
pendently and qualitatively described by the taste panel. Taste lated compounds B, C and D, for the parameters shown in Table 2. The
correction possibilities were assessed with formulation C2, O6 and O7, response factors of related compounds B, C and D were determined to
using lemon, banana, raspberry and orange essence. Raspberry and ba- allow for accurate quantification of these compounds on lorazepam cali-
nana were chosen as they are regularly applied in paediatric formula- bration curves.
tions. Lemon and orange flavours are good taste maskers for bitter
drug substances. 2.6. Calibration and sample analysis
2.4. Long-term stability studies Samples were diluted 40 times to 25 μg/ml with mobile phase and
quantified on a calibration curve (20–30 μg/ml) of freshly prepared stan-
After the preliminary formulation studies, a decision was made to dard solutions of lorazepam RS in mobile phase using the validated HPLC
continue the development with formulation O7 (Table 3). To this method. All duplicate sample analyses were preceded by a system
Fig. 3. Average lorazepam content (left graph) with SD (n = 4) and related compound C content (right graph) with SD (n = 4) of formulation O7 at 4 and 25 °C.
Conflict of interest Joint FAO/WHO Expert Committee on Food Additives, editor, 1974. Toxicological Evalua-
tion of Certain Food Additives with a Review of General Principles and of Specifica-
tions. Food and Agriculture Organization of the United Nations, Rome.
The authors have no conflict of interest to declare. Joint FAO/WHO Expert Committee on Food Additives Meeting, World Health
Organization, International Program on Chemical Safety, editors, 1982W. Toxicologi-
cal Evaluation of Certain Food Additives. WHO/FAO, Geneva.
Acknowledgements Lee, W.M., Lugo, R.A., Rusho, W.J., Mackay, M., Sweeley, J., 2004. Chemical stability of ex-
temporaneously prepared Lorazepam suspension at two temperatures. J. Pediatr.
Pharmacol. Ther. 9 (4), 254–258.
This research was supported by a ZonMW grant (project number Lee, W.M., Lugo, R.A., Cash, J., Rusho, W.J., Mackay, M., Welkie, K., 2005. The accuracy and
113202004) as part of the Priority Medicines Children program. precision of measuring Lorazepam from three liquid preparations. J. Pediatr.
Pharmacol. Ther. 10 (1), 36–42.
Lexicomp Online®, 2016. Pediatric & Neonatal Lexi-Drugs®. Lexi-Comp, Inc, Hudson,
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