Evaluation of Dantrolene Granules Extemporaneously Reformulated from Capsules in a Pharmacy

Abstract

Dantrolene capsule, an effective therapeutic agent for the treatment of spasticity, is administered to children who cannot swallow the capsule after reformulation into a powder. The powdered drug can alter the specified dosage and it is also difficult to dispense the powdered formulation because of its bulky and sticky nature. To resolve these problems, we reformulated dantrolene capsules into granules using a centrifugal planetary mixer in the pharmacy. The granules containing lactose-cornstarch, D-mannitol, or microcrystalline cellulose as a diluent were examined to determine particle size distribution, flowability, drug content uniformity, and disintegration time. The granules with microcrystalline cellulose were superior to the other forms, owing to their smaller size, good drug content uniformity, and rapid disintegration. We further investigated the usability of the granules in the dispensing procedure (dividing and packing) and in the dosing process (retrieval from package) using the powders as controls. The deviation of the divided amount and loss on dosing were reduced relative to the powders. In addition, drug dissolution properties and storage stability for 12 months were the same as those of the powders. Therefore, we concluded that dantrolene granules are excellent alternatives as an extemporaneous preparation in pharmacies.

Introduction

The need for pediatric formulations of marketed drugs has garnered increased attention.^1,2) However, clinical trials involving children are associated with unique ethical and practical issues such as patient recruitment and a need for a greater investment than similar studies in adult populations.^3,4) As a result, the unlicensed (off-label) use of medicines in children is a daily reality due to the lack of alternatives.⁵⁾ The problem not only exists in the licensing of marketed drugs for pediatric use, but also in the lack of age-appropriate formulations.⁶⁾ For children, it is occasionally difficult to swallow the solid dosage forms of most marketed drugs. Moreover, as dosing is often based on body weight, division into the necessary proportion of a solid formulation becomes difficult.

One solution is the use of extemporaneously prepared formulations in pharmacies, which are powders in Japan and solutions or syrups in the U.S.A. or EU.⁷⁾ Typically, pharmacists prepare formulations derived from solid dosage forms such as tablets and capsules. For solutions, some extemporaneous preparations have some issues regarding their limited chemical stability, microbial sterility, and storage conditions.⁸⁾ On the other hand, for powders, pharmacists added several excipients to the preparations for ease of precise weighing and division to unit-dose packages. Therefore, the resultant powders are required to fulfill standard levels of content uniformity, flowability, and storage stability. However, some extemporaneously prepared powders could not meet the grade or not be tested.⁹⁾

To resolve these issues, we proposed granules as an extemporaneous preparation for pediatric patients. These granules are produced to enhance the uniformity of the active pharmaceutical ingredient (API), facilitate weighing or dividing compounding, reduce weight loss during dispensing, reduce toxic exposure, and improve the stability of the product. Previously, some pharmacists reported that the granules were superior to powders with respect to flowability and weight loss on dispensing.^10,11) However, the manufacture of granules and assurance of their quality were difficult assignments for pharmacists in the hospital. In general, the granulation technique is broadly classified into two types: dry granulation and wet granulation, with wet granulation being the most widely used granulation technique. Currently available granulation technologies include roller compaction for dry granulation, spray drying, supercritical fluid, low/high shear mixing, fluid bed granulation, and extrusion/spheronization for wet granulation.¹²⁾ These technologies require long processing durations until the products can be used for dispensing. Therefore, we developed a concise granulation method for extemporaneous preparation using a dispensing mixer.¹³⁾ The mechanism of the machine is based on revolution-rotation motion, causing a convective force in the vessel. The added water is spread over the entire materials and then wet mass granulates via rolling in the vessel. In this method, the granulation process spends 15–90 s.

In this study, we used sodium dantrolene capsule, an effective therapeutic agent for the treatment of spasticity in children^14,15) as a model medicine. However, only capsule formulations are commercially available. Therefore, pharmacists or patients reformulated this drug to solutions in the U.S.A. and EU¹⁶⁾ or powders in Japan.¹⁷⁾ Thus, it was selected as a model medicine for this reformulation study.

The purpose of the present study was to manufacture extemporaneous granules of sodium dantrolene that were free flowing, offering rapid disintegration and were stable for an appropriate storage period. Additionally, we evaluated the granules for usability in the dispensing and dosing processes through a dividing and packaging study and a passing through a nasogastric feeding tube study. In these studies, 5% sodium dantrolene powder generated of Dantrium^® capsule content and powdered lactose was prepared and used as a control.

Experimental

Prescription Survey

We surveyed the prescriptions for inpatients and outpatients at Shizuoka Children Hospital for one year, 2018. The number of recipes that requested the reformulation of the Dantrium^® capsule into the powdered formulation and single dose amount for each patient were explored.

Materials

Dantrium^® capsules were purchased from Orphan Pacific Co. (Tokyo, Japan). Powdered lactose (Pfizer Co., Ltd., Tokyo, Japan), cornstarch (Pfizer Co., Ltd.), D-mannitol (FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan), and microcrystalline cellulose powder (less than 38 µm) (MCC, FUJIFILM Wako Pure Chemical Corporation) were used as diluents. Sodium carboxymethylcellulose (CMC, FUJIFILM Wako Pure Chemical Corporation) and talc (Kenei Pharmaceuticals Co., Ltd., Osaka, Japan) were used as the binder and lubricant, respectively. Sodium dantrolene was obtained from FUJIFILM Wako Pure Chemical Corporation. Ultrapure water was generated by an arium^®-mimi Plus (Sartorius Co., Ltd., Tokyo, Japan) and used. All other chemicals were of analytical grade and used as received.

Preparation of 5% Sodium Dantrolene Powder and Granules

The formulations of 5% sodium dantrolene powder and 5% sodium dantrolene granules are listed in Table 1.

Table 1. Formulation of the 5% Sodium Dantrolene Powder and Granules

Ingredient	Powder	Granule (L/S)	Granule (D-Mannitol)	Granule (MCC)
Dantrium® capsule 25 mg	20 cap	20 cap	20 cap	20 cap
(Capsule content)	(4.66 g)	(4.66 g)	(4.66 g)	(4.66 g)
Lactose	5.34 g	—	—	—
L/S	—	4.34 g	—	—
D-Mannitol	—	—	4.34 g	—
MCC	—	—	—	4.34 g
CMC	—	0.50 g	0.50 g	0.50 g
Talc	—	0.50 g	0.50 g	0.50 g
Total amount	10 g	10 g	10 g	10 g

To prepare 5% sodium dantrolene powder, the contents of twenty Dantrium^® capsules (4.66 g) and 5.34 g of lactose were mixed using a dispensing mixer (NW-N300DS, Beat Sensing Co., Ltd., Shizuoka, Japan) at a speed of 1200 rpm for 45 s in a plastic container (UG58-mL, Umano Chemical Co., Ltd., Osaka, Japan).¹⁸⁾

Granulation was conducted according to the reported procedure¹³⁾: 4.66 g of capsule contents from twenty Dantrium^® capsules, 4.34 g of diluents, and 0.5 g of CMC were weighed and poured in a plastic container (UG58-mL, Umano Chemical Co., Ltd.) and mixed using a dispensing mixer at a speed of 1200 rpm for 45 s. Thereafter, a predetermined amount of purified water was added to the mixture by a squeeze spray (Calmar fine mist spray, Tsubakimoto Kogyo Co., Ltd., Osaka, Japan). As stated in our previous paper,¹³⁾ we determined plastic limit values of the formulations using a digital force meter (DST-50N, IMADA Co., Ltd., Toyohashi, Japan), and we added water corresponding to appropriate 65% of plastic limit value. Granulation was then performed using a dispensing mixer at a speed of 1200 rpm for 45 s, followed by coating with 0.5 g of talc at a speed of 600 rpm for 20 s. The granules obtained were dried at 50°C for 4 h using a convection oven (ONW-600S, ASONE Co., Ltd., Tokyo, Japan). For the granules, a lactose-cornstarch mixture at a ratio of 7 : 3 (L/S), D-mannitol, or MCC was used as the diluent.

Yield of Granules

The yield of the granules was evaluated by weighing after drying. Dry granules were sieved through a 2360-µm sieve followed by a 75-µm sieve to remove any oversize agglomerates and fines. The obtained granules were weighed, and the yield (%) was calculated using Eq. 1.

  

(1)

The obtained granules were used for further experiments.

Measurement of Particle Size Distribution

The particle size distributions of the granules were measured by a sieving method using seventeen sieve screens (75, 106, 150, 212, 250, 300, 355, 425, 500, 600, 710, 850, 1000, 1180, 1400, 1700 and 2000 µm). The particle size distribution and accumulated average particle size (d50) were evaluated based on a log-normal distribution. The span was calculated using Eq. 2.

  

(2)

where d10 and d90 represent the cumulative 10 and 90% of particle size diameters, respectively.

Optical Observation

The powder and granules were observed under a microscope (M3, Schalar Co., Ltd., Tokyo, Japan) fitted with a 30× magnification lens (30N, Schalar Co., Ltd.).

Flowability

Four grams of the powder or granules was loaded into a 10-mL volumetric cylinder. Thereafter, the volume of the powder bed was measured before (bulk density) and after tapping until a constant value (tapped density) was observed.¹⁹⁾ Each experiment was repeated three times. Flowability was evaluated using the Hausner ratio (Eq. 3).²⁰⁾

  

(3)

Drug Content Uniformity of Each Size Fraction

Drug content uniformity analysis was carried out to evaluate the distribution of the API in the final granules in different sieve fractions. The granules were divided into six fractions: granule (L/S); < 500, 500–710, 710–1000, 1000–1400, 1400–1700, and 1700–2000 µm, granule (D-mannitol); < 710, 710–1000, 1000–1400, 1400–1700, 1700–2000, and 2000–2360 µm, granule (MCC); < 150, 150–300, 300–500, 500–710, 710–1000, and 1000–1400 µm. The frequency (%) and drug content of each fraction were determined. Approximately 100 mg of sample was dissolved in 100 mL of a mixture of water and methanol (4 : 6) and analyzed by HPLC as described in Section “Determination of Sodium Dantrolene by HPLC.” All experiments were performed in triplicate.

Disintegration Test

The disintegration test was carried out according to a prior report.²¹⁾ The granules, each containing 50 mg of sodium dantrolene, were mixed with 20 mL of distilled water in a 20-mL catheter syringe (Nipro Co., Ltd., Osaka, Japan) by revolving the syringe end-to-end fifteen times per 60 s. The revolution was repeated until all granules were disintegrated, and the time needed for disintegration was recorded.

In Vitro Dissolution Profiles

Dissolution profiles were examined according to the dissolution test (paddle method) of the Japanese pharmacopeia 17th Ed.²²⁾ using a dissolution apparatus (NTR-6100 A, Toyama Sangyo Co., Ltd., Osaka, Japan). The dissolution medium (900 mL) was ultrapure water, and the temperature was maintained at 37 ± 0.5 °C. The paddle speed was set to 50 rpm. Sodium dantrolene granules (0.5 g) or powder (0.5 g) were added to the dissolution medium. The sample medium was collected at 15, 30, 45, 60, and 90 min and then filtered through a 0.45-µm filter (Minisart RC15, Sartorius Japan K. K., Tokyo, Japan) prior to analysis. The amount of dissolved drug was analyzed using HPLC as described below. All experiments were performed in triplicate.

Determination of Sodium Dantrolene by HPLC

The concentration of sodium dantrolene was analyzed using an HPLC system (Shimadzu Co., Kyoto, Japan) consisting of a pump (LC-10AS), a sample injector (SIL-10A), and a UV-Vis spectrophotometric detector (SPD-10A). A C18 column (TSKgel ODS-100 V, 3 µm, 4.6 mmϕ ×150 mm, Tosoh Co., Tokyo, Japan) was used for separation, and dantrolene was detected at 380 nm. The mobile phase was 25 mM phosphate buffer (pH 3.5) with methanol (50 : 50, v/v).²³⁾

Usability of Dispensing and Dosing

To evaluate the usability upon dispensing, we performed a dividing and packing study.²⁴⁾ Briefly, 2.5 g of samples were divided into 10 packages using an automatic dividing and packing machine (io-9090EX4, Tosho Co., Ld., Tokyo, Japan).

Weight-loss (%) upon dividing and packing was calculated by the difference of the measured amount from the theoretical one.

  

(4)

When loss (%) was less than 2%, we considered satisfactory quality.²⁴⁾

The amount of medicine in each unit-dose package was determined according to Eq. 5.

  

(5)

Thereafter, the coefficient of variance (CV%) of the medicine amount in unit-dose packages was calculated using Eq. 6.

  

(6)

CV% was considered sufficient when under 6.1%.²⁴⁾

We considered the amount of medicine taken out of package as the amount of dosing. Therefore, weight-loss upon dosing was an important parameter, and was calculated using Eq. 7.

  

(7)

Drug Recovery after Passing through a Nasogastric Feeding Tube

The sample solution for the simple suspension method²⁵⁾ was prepared by adding 0.5 g of 5% sodium dantrolene granule or powder in an injector, aspirating 20 mL of hot water into the injector, and leaving this mixture for 10 min to prepare the suspension. Thereafter, the sample solution was passed through a nasogastric feeding tube (8Fr, 120 cm, Covidien Japan Co., Ltd., Tokyo, Japan), followed by flushing of the tube with 20-mL distilled water and air. The solutions passed through the tube were collected in a 100-mL measuring flask and filled with methanol. Dantrolene concentration in the solution was determined using HPLC (see section “Determination of Sodium Dantrolene by HPLC”).

Storage Stability

The formulations were protected from light, and kept under the environmental conditions of 25 ± 5 °C and 50 ± 5% relative humidity for a period of 12 months. The samples were withdrawn at 3-, 6-, and 12 months intervals and assayed for drug content using HPLC (see section “Determination of Sodium Dantrolene by HPLC”).

Statistical Analysis

A comparison of the mean values of the properties of granules was performed by one-way ANOVA followed by Tukey’s test for multiple comparisons. Comparison between granules (MCC) and the powder formulation was conducted using Student’s t-test. Differences between groups were considered significant when the p value was less than 0.05.

Results

Prescription Survey

The 31 prescriptions ordered to transform the Dantrium^® capsule to a powder formulation was derived from Shizuoka Children’s Hospital. The dose ingested by patients was varied from 0.17 to 0.75 capsules, and the median value was 0.49 capsules. Therefore, we decided that the drug containing the percent of reformulated preparations was 5%: this is because the median amount of product in one unit-dose package should be 0.245 g. Further, 0.2–1.0 g was considered to be an appropriate amount in a package.

Characteristics of the Granules

The 5% sodium dantrolene granules and powder were prepared according to Table 1. Optical images of the granules and powder are shown in Fig. 1.

Fig. 1. Images of the Powder and Granules Captured with a Microscope (30×)

(a) Powder, (b) Granule (L/S), (c) Granule (D-mannitol), and (d) Granule (MCC) black bars indicate 2000 µm. (Color figure can be accessed in the online version.)

The 5% powder showed clear orange color derived from sodium dantrolene despite the dilution with excipients. Dantrium^® capsule contains lactose, cornstarch, talc, magnesium stearate, and sodium dantrolene.²⁶⁾ The granules were almost spherical in shape and had a smooth surface with slightly orange color. However, differences in size were noted.

The particle size distribution of the granules was tested using a series of standard sieves. The results are summarized in Table 2.

Table 2. Characterization of the 5% Sodium Dantrolene Granules Prepared with Different Diluents

Sample	d10 (µm)	d50 (µm)	d90 (µm)	Span	Yield (%)
Granule (L/S)	449 ± 190	1042 ± 215	1437 ± 220†	0.98 ± 0.21	94.1 ± 1.2
Granule (D-Mannitol)	704 ± 265	1461 ± 242	1937 ± 142†	0.89 ± 0.26	95.6 ± 1.0
Granule (MCC)	153 ± 61	488 ± 59*	763 ± 49†	1.28 ± 0.27	94.1 ± 4.3

Values represent the mean ± standard deviation (S.D.) of three preparations. A significant difference was observed between the granule (D-mannitol) and granule (MCC) (* p < 0.05, Tukey’s test). Significant differences were observed between all combinations (^† p < 0.05, Tukey’s test).

The size of the granules (L/S) and granules (D-mannitol) were relatively large and in general, these diluents made the wet mass higher plasticity, leading to easy coalescence between granules.²⁷⁾ Thus, the d50 of granules (MCC) was significantly small among the three types of granules. Granules containing MCC were reported to shrink during drying.²⁸⁾ Therefore, the resultant granules became fine particles. The span value of the granule (MCC) was slightly large, indicating its inconsistent granule growth. However, the yields of the granules were similar with high recovery.

The flowability of the products was evaluated using the Hausner ratio listed in Table 3.

Table 3. Flowability of the 5% Sodium Dantrolene Granules Prepared with Different Diluents

Sample	Bulk density	Tapped density	Hausner ratio
Powder	7.32 ± 0.102	4.86 ± 0.114	1.51 ± 0.033
Granule (L/S)	5.26 ± 0.085	4.67 ± 0.024	1.13 ± 0.018*
Granule (D-Mannitol)	5.35 ± 0.068	4.80 ± 0.041	1.12 ± 0.008*
Granule (MCC)	6.71 ± 0.099	5.78 ± 0.021	1.16 ± 0.015*

Values represent the mean ± S.D. of three determinations. Significant differences were observed relate to the powder (*; p < 0.05, Tukey’s test).

All granules showed good flowability against the sodium dantrolene powder. However, there was no significant difference among the granules. Overall, the granule formulations were well prepared from the capsule content by the present granulation method and demonstrated good flowability.

Drug Content of Each Size Fraction

An important quality of granules is the consistency in the drug content of each size fraction. We examined the fractional drug content after separation by size using a series of standard sieves. The drug contents of each size fraction, with frequency, are summarized in Tables 4–6.

In Table 4, the drug content of the largest fraction (1700–2360 µm) was 85.5%, despite the high frequency of 18.9%. In Table 5, the drug content of the lower fractions, 710–1000 µm, showed a low value of 87.5%. These results indicate that granules (L/S) and granules (D-mannitol) were low uniformity for clinical use. In the agitation granulation, fractional drug content does not tend to be uniform.²⁹⁾ However, in Table 6, the granule (MCC) showed good consistency in the fractional drug content (95–105%) and sufficient for clinical use. This was because MCC led to rapid agglomeration before the segregation of excipients.

Table 4. Drug Content of Each Size Fraction of the Granules (L/S)

Particle size fraction (µm)	Frequency (%)	Content (%)
1700–2360	18.9 ± 10.9	85.5 ± 4.1
1400–1700	15.0 ± 5.1	100.3 ± 7.6
1000–1400	25.4 ± 3.4	96.7 ± 4.4
710–1000	19.6 ± 5.5	97.6 ± 8.7
500–710	12.4 ± 7.5	97.2 ± 10.6
< 500	8.7 ± 6.6	88.3 ± 4.8

Values represent the mean ± S.D. of three preparations.

Table 5. Drug Content of Each Size Fraction of the Granules (D-Mannitol)

Particle size fraction (µm)	Frequency (%)	Content (%)
2000–2360	19.2 ± 7.7	98.0 ± 11.3
1700–2000	18.9 ± 8.5	98.2 ± 11.2
1400–1700	20.6 ± 3.5	100.0 ± 3.8
1000–1400	23.9 ± 3.4	90.8 ± 10.8
710–1000	11.2 ± 8.7	87.5 ± 5.9
< 710	6.2 ± 8.7	n.d.

Values represent the mean ± S.D. of three preparations. n.d.; this could not be determined as the sample amounts were too small to assay the API content.

Table 6. Drug Content of Each Size Fraction of the Granule (MCC)

Particle size fraction (µm)	Frequency (%)	Content (%)
1000–1400	10.2 ± 1.9	100.7 ± 5.7
710–1000	23.1 ± 3.7	102.6 ± 6.8
500–710	22.6 ± 4.4	103.6 ± 8.7
300–500	23.9 ± 2.1	101.1 ± 6.1
150–300	17.1 ± 6.9	103.9 ± 4.6
< 150	3.1 ± 2.3	n.d.

Values represent the mean ± S.D. of three preparations. n.d.; this could not be determined as the sample amounts were too small to assay the API content.

Disintegration Test

In clinical settings, the formulation is suspended in water before being administered through a nasogastric tube. It is necessary to disintegrate it over a short time. Therefore, we investigated the disintegration of granules in water. The time required for complete disintegration is listed in Table 7.

Table 7. Disintegration Time of the 5% Sodium Dantrolene Granules Prepared with Different Diluents

Sample	Disintegration time (min)
Granule (L/S)	8.3 ± 0.5*
Granule (D-Mannitol)	8.0 ± 0.8*
Granule (MCC)	5.3 ± 0.5

Values represent the mean ± S.D. of three determinations. Significant differences were found compared with the granule (MCC) (*; p < 0.05, Tukey’s test).

The granules (MCC) spent a significantly shorter time than the other formulations. In general, MCC works as a disintegration agent due to its highly hygroscopic nature. Thus, granules (MCC) was recognized to be superior to granules (L/S) and granules (D-mannitol) for disintegration.

Dissolution Behavior

The drug dissolution behaviors from the granules and powder were investigated for bioequivalence. Figure 2 shows the dissolution profiles of sodium dantrolene from the formulation.

Fig. 2. Dissolution Profiles of Sodium Dantrolene from the Powder and Granule Formulations in Water (37 °C)

Each point represents the mean ± S.D. (n = 3).

During the first 15 min, all granules disintegrated and released almost 100% of the dissolved drug. Such finding indicated that the granules would be bioequivalent to the powder used in the present study.

Usability on Dispensing

Based on the above results, we decided that the granules (MCC) were appropriate formulations for clinical use and sought to compare the granules (MCC) to the powder.

The usability upon dispensing was evaluated using weight loss in the dispensing process and variation of the drug amount in the unit-dose package. The results are presented in Table 8.

Table 8. Weight Loss and Dose Deviation during the Dispensing Process

Formulation	Weight loss (%)	CV% of unit-dose package (%)
5% Powder	1.35 ± 0.14	1.04 ± 0.16
5% Granule (MCC)	0.72 ± 0.17*	0.95 ± 0.15

Values represent the mean ± S.D. of three determinations. A significant difference was found between the powder and granule (* p < 0.05, t-test).

The weight loss (%) of granules (MCC) was lower than that of the powder. CV% showed a low value in both formulations. In general, weight loss was caused by dispersion and adherence to the dividing and packing machine.^30,31) Such finding indicates that granules (MCC) were hard to scatter and adhere to the apparatus during the dispensing process.

Usability on Dosing

The usability upon dosing was evaluated using weight loss in the dosing process and variation in the amount of medicine retrieved from the unit-dose package (Table 9).

Table 9. Weight Loss and Dose Deviation during the Dosing Process

Formulation	Weight loss (%)	CV% of dosing amount (%)
5% Powder	3.77 ± 0.25	3.65 ± 0.60
5% Granule (MCC)	0.23± 0.05*	3.44 ± 0.45

Values represent the mean ± S.D. of three determinations. A significant difference was found between the powder and granule (* p < 0.01, t-test).

The weight loss (%) of granules (MCC) was significantly lower than that of the powder. Further, the CV% of the dosing amount showed a similar value in both formulations. The powder tended to adhere to the package.³²⁾ However, the granules did not remain in the package. With respect to handling during the process of dispensing and dosing, the granules were superior to the powder formulation for the administration of a precise dose.

Drug Recovery after Nasogastric Dosing

Sodium dantrolene powder reformulated from the capsules is frequently administered to pediatric patients through a nasogastric tube. Therefore, we examined its potential to permeate the nasogastric tube and the ability of the drug content in the solution to permeate the nasogastric tube (Table 10).

Table 10. Passing Potential and Drug Recovery upon Dosing via a Nasogastric Tube

Formulation	Potential of passing	Drug recovery (%)
5% Powder	Possible	102.2 ± 6.7
5% Granule (MCC)	Possible	99.2 ± 4.2

Values represent the mean ± S.D. of three determinations. There was no significant difference between the two formulations (t-test).

The granules could disperse in water and permeate the tube and powder. In both formulations, drug recovery was sufficient for clinical use. Owing to this result, the granules were employed instead of the powder.

Storage Stability

When medicine is used in clinical situations, the storage stability of the API must be maintained during the drug-taking interval. We assayed the API content of the granules (MCC) and powder for 12 months. Table 11 shows the API content against the theoretical content of the formulations.

Table 11. Storage Stability Examined by Retaining the Mass (%) of Sodium Dantrolene in the Formulations

Formulation	3 Months	6 Months	12 Months
5% Powder	101.6 ± 3.9	101.9 ± 2.8	97.6 ± 5.3
5% Granule (MCC)	104.2 ± 9.4	100.9 ± 4.5	100.7 ± 5.0

Data are expressed as the mean ± S.D. of five determinations. There was no significant difference between the two formulations (t-test).

Both formulations showed good stability for 12 months, with sufficient interval for the completion of drug intake.

Discussion

In this study, we reformulated sodium dantrolene granules from commercially available sodium dantrolene capsules using a dispensing mixer. This granulation method was concise and efficient for extemporaneous preparation with a high yield and narrow span (Table 2). The granules obtained were almost spherical and free-flowing (Table 3). In addition, weight loss upon dispensing and dosing was suppressed for the granule (MCC) compared to its powder (Tables 8, 9) as its formulation is generally less cohesive and disperse than that of the powder formulation in general. From the viewpoint of equivalence, the granule (MCC) showed good ability to permeate the nasogastric tube (Table 10) and undergo rapid drug dissolution (Fig. 2), similar to the powder. Moreover, the long-time storage stability of the granules was confirmed (Table 11).

The findings of this study shed light on methods that can be used to obtain an alternative formulation to powders or liquids for pediatric patients. In powders, issues of cross-contamination and weight loss are unavoidable while in solutions or syrups, drug stability and bacterial contamination are major hurdles for long drug-taking intervals.⁸⁾ Conversely, granules could resolve those issues relatively with ease. The granules are also superior to the formulations owing to their usability for dispensing and dosing. Furthermore, high patient acceptability was recognized for multiparticulates such as small pellets and beads.³³⁾ Thus, the granules were recommended when the powders and liquids were inappropriate for extemporaneous preparations.

Previously, granules were prepared as hospital formulations.¹⁰⁾ However, this is rarely performed in pharmacies as the granulation method is time-consuming and labor intensive. The present methodology is different from ordinary granulation methods. First, less than 5 h, including a long procedure, was required to obtain the final products. Using this preparation method, pharmacists who accept the doctor’s receipt could prepare granules on demand on the same day.

This study had several limitations. First, sodium dantrolene was the only model medicine. However, three excipients such as L/S, D-mannitol, and MCC, were employed as fillers to prepare granules with good properties in this study. Overall, MCC was found to be effective for achieving product consistency in the drug content (Table 6) and rapid disintegration of the granules (Table 7). Therefore, many attempts at granulation can be carried out by selecting adequate excipients for the candidate medicine. Nevertheless, there remains some discussions regarding its use for moisture-sensitive drugs or high drug loading. Generally, during formulation development, each drug substance poses a unique challenge that must be considered at the process selection stage by formulation development scientists.

In conclusion, the present methodology will allow pharmacists to select granule formulation as an extemporaneous preparation for pediatric patients who are unable to swallow capsules.

Acknowledgments

This study was partially supported by the Japan Society for the Promotion of Science KAKENHI Grant number JP19K07169. We thank Beat Sensing Co., Ltd. for leasing the dispensing mixer.

Conflict of Interest

The authors declare no conflict of interest.

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