Next Article in Journal
Dendrimers and Dendritic Materials: From Laboratory to Medical Practice in Infectious Diseases
Next Article in Special Issue
Development of a Curcumin-Loaded Polymeric Microparticulate Oral Drug Delivery System for Colon Targeting by Quality-by-Design Approach
Previous Article in Journal
Low-Vacuum Filtration as an Alternative Extracellular Vesicle Concentration Method: A Comparison with Ultracentrifugation and Differential Centrifugation
Previous Article in Special Issue
Phytol-Loaded Solid Lipid Nanoparticles as a Novel Anticandidal Nanobiotechnological Approach
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmaceutics
Volume 12
Issue 9
10.3390/pharmaceutics12090873
pharmaceutics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Development of a Solid Formulation Containing a Microemulsion of a Novel Artemisia Extract with Nematocidal Activity for Oral Administration

by
Ines Perez-Roman
1,
Filip Kiekens
2,
Damian Cordoba-Diaz
1,3,
Juan Jose Garcia-Rodriguez
4 and
Manuel Cordoba-Diaz
1,3,*
1
Department of Pharmaceutics and Food Technology, Complutense University of Madrid, Pza. Ramón y Cajal s/n, E-28040 Madrid, Spain
2
Department of Pharmaceutical Sciences, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, Wilrijk, 2610 Antwerp, Belgium
3
University Institute of Industrial Pharmacy (IUFI), Complutense University of Madrid, Pza. Ramón y Cajal s/n, E-28040 Madrid, Spain
4
Department of Microbiology and Parasitology, Complutense University of Madrid, Pza. Ramón y Cajal s/n, E-28040 Madrid, Spain
*
Author to whom correspondence should be addressed.
Pharmaceutics 2020, 12(9), 873; https://doi.org/10.3390/pharmaceutics12090873
Submission received: 30 July 2020 / Revised: 9 September 2020 / Accepted: 10 September 2020 / Published: 14 September 2020
(This article belongs to the Special Issue Natural Products in Drug Delivery Systems)
Browse Figures
Versions Notes

Abstract

:
Background: Intestinal nematode infections are usually treated with benzimidazole drugs, but the emergence of resistance to these drugs has led to an increasing demand of new anthelmintic strategies. A new microemulsion formulation (ME) consisting of an Artemisia absinthium extract with proven nematocidal efficacy was previously developed. The aim of our study is to implement a D-optimal mixture design methodology to increase the amount of a silica material (loaded with this ME) in a tablet formulation, considering its tensile strength and disintegration time. Methods: 16 experiments or combinations of the 6 tablet components (loaded silica, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose, Syloid® 244 FP and magnesium stearate) were assessed. Tensile strength and disintegration time models were developed, and an optimization process was carried out. Results: Tensile strength was improved by increasing the polyvinylpyrrolidone content, while croscarmellose decreased the disintegration time. The optimized powder mixture contains 49.7% w/w of the loaded silica material. A compression force of 12 kN was applied to the powder mixture to form tablets with a tensile strength of 2.0 MPa and a disintegration time of 3.8 min. Conclusions: Our results show that D-optimal mixture designs provide a promising approach to formulate liquid-loaded silica materials.

Graphical Abstract

1. Introduction

Intestinal nematode infections are usually treated with benzimidazole drugs, but recent studies [1] have evidenced a worrying increase of the cases of resistance to these drugs leading to potential failures of the commonly used therapies. This illustrates the importance of searching for new alternative strategies for the treatment of these kinds of illnesses. As a consequence, medicinal plants have been shown to be a promising source of new anthelmintic treatments [2]. Some species of Artemisia have been traditionally used to control this kind of infection; the anthelmintic efficacy of Artemisia absinthium has been extensively demonstrated [3]. However, the presence of toxic thujones within the extracts of Artemisia constitutes an important drawback for their clinical use. In previous studies, our group developed a new microemulsion (ME) for the vehiculization of thujone-free extracts of Artemisia absinthium developed by the Research Institute of Agricultural Sciences (ICA) in Zaragoza (Spain). The original steam distillation extract was previously characterized by GC–MS and the presence of (Z)-epoxyocymene, chrysanthenol, (E)-caryophyllene and linalol as main components was evidenced [4].
Nematocidal activity of the microemulsion containing the Artemisia extract was also demonstrated in our previous studies [4,5] using an ex vivo murine model for Trichinella spiralis larvae. In fact, the microemulsion system provided a (more than) 95% decrease of the intestinal parasites compared to the original extract. This improvement was also associated with the higher dispersibility of the microemulsion in gastric fluid in comparison to the pure oily extract. This was evidenced through the in vitro dissolution tests, performed according to USP 32 simulating fasting conditions, as described in the same previous study [4].
The adsorption of liquids in solid carriers, transforming them into free-flowing powders, is one of the possible approaches to solidify liquid formulations [6,7]. Solid carriers with a high surface area can be loaded with liquid two or three times their weight without altering their flow properties [6]. Among the materials commonly used in oral formulations [8,9], non-ordered mesoporous silica gel (Syloid® XDP) has shown a good absorption and desorption capacity [10,11,12]. There are two types of Syloid® XDP commercially available, 3050 and 3150, both having a high pore volume (1.7 cm3/g) and a high surface area (320 m2/g).While Syloid® XDP 3150 has higher average particle size (150 µm) than Syloid® XDP 3050 (50 µm), both are able to retain a high amount of liquid [13,14]. Syloid® XDP 3150 shows better flow properties, improving the content uniformity and the formulation of loaded silica in tablets [15,16].
Tablets are the most widely used solid form, as they improve the dosage of pharmaceutical compounds [17]. However, when silicate powders are compressed into tablets, they usually show low tablet hardness due to their poor compressibility properties. Tablet formulations of liquid-based drug delivery systems also exhibit high disintegration times. One of the reasons is the hydrophobic environment created by some of the components of the liquid formulations that prevents the contact with water molecules and the release of the active substances [18]. As a consequence, the development of tablets based on liquid-loaded silica materials requires the inclusion of binders, but also disintegrants are necessary.
Direct-compression is a tablet manufacturing process with well-known advantages in the pharmaceutical industry, as it requires fewer processing stages and a reduction of the final product cost. However, the powder mixture should have acceptable flow and compression properties in order to obtain tablets with content uniformity and adequate physical characteristics [19,20,21,22].
A direct-compressed tablet formulation based on Syloid® XDP is already published [11], consisting of vitamin E-loaded Syloid® XDP (1:1), microcrystalline cellulose (MCC) PH102, pregelatinized starch, croscarmellose sodium (CCMNa), Syloid® 244 FP and magnesium stearate (MgSt). This powder mixture needs a compression force of 20 kN to produce tablets with adequate properties (hardness: 60 N (tensile strength ≈ 1.6 MPa) and disintegration time: 1 min) [11,16]. However, high compression forces may squeeze the absorbed liquid out of the liquid-loaded silica tablets; therefore, compression forces should be lowered and binders must be incorporated to the powder mixture [23].
Mattsson et al. showed that powder mixtures containing polyvinylpyrrolidone (PVP), as a dry binder, and compressed at 200 MPa had higher axial and radial tensile strength than pregelatinized starch mixtures at the same proportion [24]. These results suggest that PVP may improve the tensile strength of silica tablets, although an efficient disintegrant is required to diminish disintegration times, improving the galenic properties [23].
Response surface methodologies, such as mixture designs, have recently been used in the formulation of microemulsions (ME) [25,26,27], self-emulsifying drug delivery systems (SEDDS) [28,29,30], liposomes [31,32] and tablets [19,33,34,35,36,37,38]. The D-optimal design is one of the most used methodologies in this field, because it allows different composition constraints, in which the sum of all components is constant (100% w/w). Secondly, it also estimates the excipients’ effects on the formulation characteristics, thus permitting the optimization of the whole system [34,39].
Although ME or SEDDS are already currently used to formulate essential oils with therapeutic properties [40,41], there is increasing interest in loading liquid formulations in solid carriers to improve their doses [12,17] and to obtain the most stable and easy to use solid dosage forms.
In the light of this, the main objective of this work was to focus on the design and optimization of an oral formulation for the treatment of intestinal nematode infections containing an ME of a thujone-free lipidic extract of Artemisia absinthium in directly compressible tablets.
Due to the fact that the load of a liquid formulation is usually the limiting step in the development of a solid formulation, the implementation of a D-optimal mixture design to increase the amount of a loaded silica material (e.g., Syloid® XDP 3150: ME) in a tablet formulation is proposed as an interesting tool for the rational and effective development of an acceptable formulation, according to different pharmaco-technical parameters such as tensile strength (as a measure of tablet hardness) or disintegration time.

2. Materials and Methods

2.1. Materials

The ME was prepared with a surfactant–co-surfactant mixture composed of Tween® 80:propylene glycol (1.5:1 w/w); both products were purchased from Acofarma Distributions, S.A. (Madrid, Spain). The Artemisia absinthium extract (AAE) was provided by the Research Institute of Agricultural Sciences (ICA) (Madrid, Spain). It was obtained by vapor pressure extraction using a stainless-steel industrial distillation plant [38]. The resulting extract is composed by mono- and di-terpene components with promising nematocidal properties [39]. Milli-Q® (Merck-Millipore, Madrid, Spain) water was used throughout all the experiments.
Regarding the solid excipients, PVP K30 (MW 40 kDa) and MCC, Ph. Eur. (Avicel® PH102) were acquired from Merck (Overijse, Belgium). CCMNa, NF (Ac-Di-Sol®) was obtained from FMC Health and nutrition (Philadelphia, PA, USA). MgSt Ph.Eur. was purchased from Omega pharma NV (Zwevegem, Belgium). Mesoporous silica gel (Syloid® XDP 3150) and colloidal silicon dioxide (Syloid® 244 FP) were provided by Grace Davison (Worms, Germany).

2.2. Methods

2.2.1. Formulation of a Microemulsion Containing the Artemisia absinthium Extract

The ME containing the AAE was previously developed and optimized using a D-optimal mixture design, based on its droplet size distribution and conductivity properties. The optimized ME consisted of 66.40% w/w of the surfactant mixture, 29.35% w/w of an AAE and 4.25% w/w of water. The ME formulation was prepared by mixing all the components—at the concentrations previously indicated—under constant stirring for 5 min at 100 rpm using an AGIMATIC-N (Selecta Group, Barcelona, Spain) magnetic stirrer, as described in our previous study [4].

2.2.2. Characterization of the Loaded Syloid® XDP System

Silica material (Syloid® XDP 3150) was loaded with the ME formulation, at a proportion of 1:1.5 w/w in a beaker with the help of a spatula [18]. Next, the powder mixtures were kept stable for 24 h in a sealed beaker to ensure complete absorption of the liquid formulation in the carrier, according to the methodology proposed by Choudhari et al. [12].
Flow properties of the neat and loaded Syloid® XDP were assessed. Bulk density (ρb) and tapped density (ρt) were determined, as indicated in USP 38 [41], using a Jel Stav 2003 equipment (J. Engelsmann AG, Ludwigshafen am Rhein, Germany). Compressibility index and Hausner ratio were also calculated, using the following equations [42]:
Compressibility index = (100 (ρt − ρb))/ρt
Hausner ratio = ρt/ρb
In order to calculate the angle of repose (α), powder was passed through a funnel placed 10 cm over a plain surface. The funnel was 220 mm high, with a diameter of 212.5 mm; the stem was 122 mm long and it had a diameter of 12 mm. The cone formed by the powder mixture was measured, and the angle was assessed using the following equation [42]:
tan(α) = height/0.5 base
These measurements were repeated three times.

2.2.3. Selection of the Binder, Binder Content and Compression Force

The efficacy of PVP and pregelatinized starch as dry binders was assessed. Based on the previously published formulation, two mixtures were prepared: one included 10% w/w of PVP and the other, 10% w/w of pregelatinized starch; the other components were Syloid® XDP:ME (1:1.5) (40.0% w/w), MCC PH102 (45.5% w/w), CCMNa (3.0% w/w), Syloid® 244 FP (1.0% w/w) and MgSt (0.5% w/w) [11]. Excipients were combined using a Turbula® T2F (Willy A. Bachofen AG Maschinenfabric, Muttenz, Switzerland) mixer. Mixtures were passed through a 60-mesh sieve. Tablets were made by direct-compression using an EZ20 (Lloyd Instruments Ltd., Bognor Regis, UK) universal testing machine and a 9 mm-diameter round flat die. The compression forces were 10 kN, 12 kN and 15 kN.
Tablets were analyzed for their tensile strength, according to the formula of Fell and Newton [43]:
σ = 2F/πDH
where σ is the tensile strength, F is the breaking force, D is the tablet diameter and H is the tablet thickness. The breaking force of the tablets was determined from the diametral-crushing force, using a PTB411 hardness tester (Pharmatest, Hainburg, Germany). The tensile strength tests were repeated ten times. The binder with better results (considering a tensile strength over 1 MPa as a minimum level of acceptance) was selected for further research [16], and it was included at 10% w/w, 15% w/w or 26.5% w/w content; the powder mixture was compressed at 12 kN or 15 kN.

2.2.4. Optimization of a Tablet Formulation Based on a Syloid® XDP:ME System

The tablet formulation was optimized using a D-optimal mixture design. The independent variables were the amount of loaded carrier and excipients (MCC PH102, CCMNa, Syloid® 244 FP and MgSt), which were set within their composition ranges, to fit a linear, distance-based model (Table 1) [44].
The amounts of the 6 components were varied simultaneously and the whole concentration was adjusted to 100% w/w; 16 experiments or combinations of the 6 components were assessed. Each experiment was prepared by mixing the components. Powder mixtures were analyzed according to their flow properties. Bulk density and tapped density were measured in the same way as in previous experiments. Then, mixtures were compressed into tablets applying a 12 kN force. All tablet samples were elaborated adjusting the process to obtain the same weight (171 mg).
Tablets were analyzed for their tensile strength and disintegration time. Tests were performed with 6 tablets of each formulation. Disintegration tests were performed using a tablet disintegration tester (Vanderkamp 71b-174B-6; Vankel Industries, INC., Chatham, Ontario, Canada) with 900 mL of distilled water at 37 °C. The disintegration time was expressed as the time (in minutes) in which all tablets disintegrated within a timeframe of 15 min as the limit of acceptance.
Design Expert® (version 7, Stat-Ease Inc, Minneapolis, MN, USA) was used to develop and evaluate the tensile-strength and disintegration-time models. An optimization process of the tablet formulation was carried out in order to find the best compromise between the amount of extract and the tablet properties. The optimal formulation was selected as that having the highest tensile strength and the lowest disintegration time, along with the highest amount of Syloid® XDP:ME.
The optimal formulation assessed by Design Expert® was analyzed in our laboratory, and the statistically predicted results were compared to the actual results, assessing the relative standard error (RSE):
RSE (%) = |((Actual value − Predicted value)/Predicted value)| × 100

3. Results

3.1. Characterization of the Loaded Syloid® XDP

The Syloid® XDP:ME system showed a free-flowing appearance without any aggregates (Figure 1A). Its morphology was observed using a light microscope at 40× and 100× (Figure 1B,C). Densities of the neat carrier and the loaded system are shown in Table 2. As can be seen, loaded Syloid® XDP showed higher densities (ρb and ρt), compressibility index and Hausner ratio than the neat silica. According to the USP classification [42], flow properties of the neat Syloid® XDP were “Good”, and those of the loaded silica were “Fair”. Therefore, the loaded system could be further formulated into tablets.

3.2. Selection of the Binder, Binder Content and Compression Force

The tensile strength results, depicted in Figure 2, illustrated that tablets containing PVP showed an increase in tensile strength along with the PVP content. However, those changes were hardly seen in pregelatinized-starch tablets, and none of them reached the minimum tensile strength (1 MPa) [16].
As a consequence, the most appropriate binder for further research was PVP. It was included in tablets at 10% w/w, 15% w/w and 26.5% w/w (Figure 2B). The results showed that the tensile strength increased along with the binder content and the compression force. The minimum tensile strength was observed at PVP 10% w/w, after applying the highest compression force (15 kN). However, a higher amount of PVP (15% w/w) reduced the compression force required to form tablets with a 1-MPa tensile strength. Therefore, a 15% w/w amount of PVP and a compression force of 12 kN were selected for further research.

3.3. Development of Model Equations

The composition of the experiments and their responses are indicated in Table 3. As can be seen, some of the experiments were performed with the same composition in order to evaluate the model’s accuracy.
The compressibility index of the formulations ranged from 7.69 to 20.45, and the Hausner ratio from 1.06 to 1.28 (Table 4). Most of the formulations had flow properties classified as “Excellent”, “Good” or “Fair” [42]. As could be expected, formulations with low Syloid® 244 content (experiments 10 and 12) had worse flow properties than the other formulations, while experiment 8—with a high percentage of Syloid® 244 (1% w/w)—showed a “Fair” flow behavior. This may be explained because mixture 8 contained only PVP and the loaded carrier, and no other excipients, such as CCMNa, which may improve flow behavior [44,45]. However, according to the angles of repose, all formulations had an “Excellent” flow behavior [42] and they could be compressed into tablets using a direct-compression method [20].

3.3.1. Tensile Strength

The tensile strength of the powder mixtures after compression varied from 0.14 MPa to 2.70 MPa (Table 5). Since the experiments were assessed based on a linear design, a more complex model could not fit. The linear model showed good performance (R2 = 0.9158) with low Prediction Residual Sum of Squares (PRESS) (1.75), and a reasonable proximity between predicted R2 (0.8097) and adjusted R2 (0.8690). The adequate precision was 12.34, i.e., greater than 4, which indicates an adequate signal. These results supported the validation of the model to be used for point-prediction [46,47,48].
The characteristics of the linear model are shown in Table 6. As can be seen, F-value was 19.58 (p-value = 0.0001), which implies that the model was significant. The closeness of the actual and predicted values to the diagonal line also supported this conclusion (Supplementary data, Figure S1). The normalized probability plot for residuals traced a straight line, indicating that normality assumptions were suggested for the linear model (Supplementary data, Figure S2). However, the lack of fit in the model was significant (p = 0.0063), which indicates that the model may not describe the data adequately. This may be due to the interactions among the components of the formulation that could be not elucidated in a linear model.
On the basis of these results, the following equation was obtained:
Tensile strength (MPa) = 0.0094 × Syloid® XDP:ME (1:1.5) + 0.0019 × MCC + 0.1100 × PVP + 0.0058 × CCMNa + (−1.0560) × Syloid® 244 + 1.0220 × MgSt
The magnitude of each coefficient indicates the level of contribution to the response and the positive or negative sign refers to its incremental or decreasing effect on the final response [39]. The resulting equation evidences that the most influential excipients with a positive effect on tensile strength are PVP and MgSt. As a binder, PVP makes connections among the solid particles, improving the hardness of the tablets and, as a consequence, their tensile strength [44,45].
MgSt usually decreases or has no effect on the tensile strength of the tablets [49,50,51,52]. However, our results showed that this excipient increased the tensile strength of the tablets. One of the possible explanations is that the lubricant particles—with a hydrophobic nature—formed bonds with the ME on the surface of the silica material, making the tablets denser, with higher hardness and, consequently, higher tensile strength [53].
Regarding the silica material, our results showed that the loaded Syloid® XDP had a very small but positive influence on the tensile strength of tablets, probably because the presence of the ME system on the surface of the silica particles made them to stick to each other [54]. However, as expected, Syloid® 244 did not form those bonds, so it decreased the tensile strength of tablets [55].

3.3.2. Disintegration Time

The disintegration time of the tablets varied from 0.20 min to 14.00 min (Table 5). The linear model also showed a high correlation ratio (R2 = 0.9095). The PRESS value (30.98) was higher in comparison to the previous model, and the connection between predicted R2 (0.6368) and adjusted R2 (0.8340) was not as close as in the last design. This may be explained because the influence of the excipients on the disintegration time is complex, hence a quadratic design would have a better fit than a linear design. However, the adequate precision (8.200) still validated the model to be used for point-prediction [46,47,48].
The characteristics of the linear model are shown in Table 6. As can be seen, F-value was 12.06 and p-value was 0.0044, which implied that the model was significant. The connection between predicted and actual values can be observed in the graph included in Figure S3 in the Supplementary data. The normalized probability plot for residuals traced a straight line, indicating that normality assumptions were suggested for the linear model (Supplementary data, Figure S4).
On the basis of these results, the following equation was obtained:
Disintegration time (min) = −0.0465 × Syloid® XDP:ME (1:1.5) + 0.1038 × MCC + 0.4498 × PVP + (−0.9391) × CCMNa + (−2.2973) × Syloid® 244 + 4.6572 × MgSt
The resulting equation evidences that the excipients that accelerated the disintegration of the tablets were CCMNa and Syloid® 244. CCMNa is a superdisintegrant, so it reduces the disintegration time of the tablet in aqueous environments and therefore accelerates the delivery of the active substances [44,56]. Syloid® 244 also decreased the tablet disintegration time, probably because of its poor tableting behavior [57].
On the other hand, PVP increased the tablet disintegration time, by increasing the tensile strength of the tablets [44,45]. MgSt showed a high positive influence on the disintegration time, maybe due to its lipophilic nature, which reduced the tablet wettability. A reduction in the mixing time of the MgSt may have reduced this influence [20,44,51].

3.4. Optimization of a Tablet Formulation

Previous results were used to optimize the tablet composition. The optimal formulation was composed of Syloid® XDP:ME (1:1.5) (49.71% w/w), MCC PH102 (33.56% w/w), PVP (12.55% w/w), CCMNa (3.03% w/w), Syloid® 244 FP (0.59% w/w) and MgSt (0.56% w/w). The predicted results were 1.89 (95% CI: 1.53–2.26) MPa and 5.24 (95% CI: 3.63–6.85) min for the tensile strength model and the disintegration time model, respectively. The optimal formulation was analyzed in the laboratory, and the actual tensile strength was 2.03 (95% CI: 1.65–2.42) MPa, while the disintegration time was 3.8 min (Figure 3).
There was a close connection between the predicted and the actual results. However, the RSE values were lower in the tensile-strength model (7.46%) than in the disintegration-time model (27.43%). This difference may be explained because the former has a better prediction accuracy than the latter model.

4. Discussion

This study shows a methodology to optimize a tablet formulation based on a liquid-loaded carrier, manufactured by direct compression with the main objective of developing a solid dosage form to be used for the treatment of intestinal nematode infections, from an Artemisia absinthium extract vehiculized in a microemulsion system.
It includes the following stages: (1) vehiculization of the extract by preparing a microemulsion, (2) loading the liquid formulation (ME) into the solid carrier, (3) selection of the excipients and (4) optimization of the tablet formulation.
In our study, the ME formulation was loaded in the Syloid® XDP in a 1:1.5 w/w proportion. The loaded silica material had free-flowing properties without any aggregates. These results are consistent with the assessments published by Madhav et al., who loaded 1.61 g of a liquid formulation per gram of Syloid® XDP, resulting in good flow properties [14].
Tablets made by direct-compression methods require the selection of effective excipients with good flow properties and compression behavior [58]. In our study, the selection of excipients was based on the results published by Choudhari et al. [12]. Nevertheless, silica materials have very poor tableting behavior [23] and cannot be exposed to high compression forces that may squeeze the loaded liquid out. Our results showed that powder mixtures including PVP in proportions ranging from 15% w/w to 26.5% w/w were able to form tablets showing tensile strength values of 2 MPa, applying a compression force of 12 kN.
D-optimal designs provide a different approach to the traditional formulation procedures applied in the development of tablets, as they quantify the effect of the excipients on the final formulation, under the conditions of the study [59]. They have been previously used to formulate active substances with low flowability and poor tableting behavior [19,35,36,37,38]; however, they have still not been used to develop direct-compressed tablets based on liquid-loaded silica. The main contribution of our study is the use of this methodology to formulate an ME-loaded silica tablet. Due to the poor compressibility properties of the silica material, we selected tensile strength and disintegration time as the main response variables to optimize the new formulation, as they indicate the interparticle bonding and technical characteristics of tablets [60,61]. Results showed that tensile strength was improved by the PVP content, while Syloid® 244 had a negative influence.
PVP increased the disintegration time of the tablets, while CCMNa accelerated this process. It was seen that although the content of PVP in the tablets was higher than the recommended amount (1% w/w–5% w/w) [44], it improved the tensile strength at a desirable value [17]. Furthermore, the increase in the disintegration time because of the PVP content was counteracted by the effect of the CCMNa.
An optimal formulation was assessed by the optimization software and analyzed using characterization tests. In order to compare the predicted and the actual results, we calculated the RSE as in other studies [35,36]. However, our RSE values were higher because our experiments were developed using a linear model to analyze the main interactions among the excipients.
Our optimized powder mixture needs a compression force of 12 kN to manufacture tablets with a tensile strength of 2 MPa. Although the compression force cannot be directly compared between different machines [62], we can say that our compression force is lower (12 kN) than the force that Choudhari et al. required (20 kN) to form tablets with a tensile strength of around 1.6 MPa [12]. This may be explained by the higher amount of binder (14.3% w/w) in comparison to the tablet formulation of Choudhari et al. (10.0% w/w). As could be expected, higher binder content increases the disintegration time, so our tablets needed more time (3.8 min) than theirs to disintegrate (1 min).
The optimized formulation contains a higher percentage of the loaded silica material (49.7% w/w) in comparison to the formulation developed by Choudhari et al. (40.0% w/w) [12]. Moreover, as they loaded the silica material with a 1:1 ratio (Syloid® XDP:vitamin E), the amount of liquid loaded was lower than in our formulation (20% w/w versus 29.8% w/w of ME, which implies 8.9% w/w of AAE).
Previous studies [4] evidenced that the optimized ME showed a W/O structure, but it was capable of dispersing in the gastric environment in less than 15 min, forming 10 nm-sized droplets. Considering that the optimized tablet formulation showed a disintegration time of less than 4 min, the release and dispersion of the ME in the gastric fluid was assured. It was also observed that the droplet size of the ME, once released from the tablet, was similar to the original ME system, what indicated that no incompatibility among absorbed ME and the inert excipients was found, as reported by other authors for these materials [12].
Our results show that D-optimal designs provide a promising tool to improve the formulation of liquid-loaded silica materials in tablets, as it quantifies the effect of the excipients on the properties of the tablets under the conditions of the study. However, due to the limited availability of the Artemisia absinthium extract, it was not possible to analyze the interaction of the formulation components. Therefore, more complex designs, such as quadratic models, are needed to develop a more accurate tablet formulation. Those models could probably provide better quality parameters to improve the optimization of the tablet composition. In addition, this new tablet formulation will require further research to study other pharmaco-technical properties like friability and content uniformity. The delivery characteristics of the ME, as well as the nematocidal activity of the natural extract included in these tablets, should also be investigated [63].

5. Conclusions

In this study, a D-optimal mixture design was used to improve the amount of liquid-loaded silica material in a tablet formulation. The optimized formulation met the requirements of a tensile strength greater than 1 MPa and a disintegration time lower than 15 min [63,64], providing values of 2 MPa and 3.8 min, respectively, applying a compression force of 12 kN over the mixture, while showing the maximum ME loading capacity with a content of 49.71% w/w of the loaded-silica materials.
Our results show that D-optimal mixture designs provides a promising option to formulate loaded silica materials with poor compressibility properties. Our model showed good predictability according to the adjusted and predicted R2 values, as previously described. These results provide a new approach to improve the oral dosage of liquid formulations, especially for those composed of essential oils with therapeutic properties.

Supplementary Materials

The following are available online at https://www.mdpi.com/1999-4923/12/9/873/s1, Figure S1: Predicted vs. actual values plot tensile strength model, Figure S2: Normalized probability plot tensile strength model, Figure S3: Predicted vs. actual values plot disintegration time model, Figure S4: Normalized probability plot disintegration time model, Table S1: Final report of the tensile strength model, Table S2: Final report of the disintegration time model.

Author Contributions

Conceptualization, F.K. and M.C.-D.; methodology, F.K. and I.P.-R.; software, I.P.-R.; validation, I.P.-R., M.C.-D. and J.J.G.-R.; formal analysis, F.K., M.C.-D. and D.C.-D.; investigation, I.P.-R.; resources, F.K.; data curation, I.P.-R. and F.K.; writing—original draft preparation, I.P.-R., M.C.-D. and D.C.-D.; writing—review and editing, M.C.-D., D.C.-D. and J.J.G.-R.; visualization, I.P.-R.; supervision, F.K. and M.C.-D.; project administration, F.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

The authors wish to thank A. González-Coloma (ICA, Madrid) for the donation of the AAE for the development of these studies.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Moser, W.; Schindler, C.; Keiser, J. Efficacy of recommended drugs against soil transmitted helminths: Systematic review and network meta-analysis. BMJ 2017, 358, j4307. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Preston, S.; Gasser, R.B. Working towards new drugs against parasitic worms in a public-development partnership. Trends Parasitol. 2018, 34, 4–6. [Google Scholar] [CrossRef] [PubMed]
  3. Beshay, E.V.N. Therapeutic efficacy of Artemisia absinthium against hymenolepis nana: In vitro and in vivo studies in comparison with the anthelmintic praziquantel. J. Helminthol. 2018, 92, 298–308. [Google Scholar] [CrossRef] [PubMed]
  4. Perez-Roman, I.; Garcia-Rodriguez, J.; Kiekens, F.; Cordoba-Diaz, D.; Diaz, M. Enhanced nematocidal activity of a novel artemisia extract formulated as a microemulsion. Nat. Prod. Commun. 2019, 14, 1–6. [Google Scholar] [CrossRef]
  5. García-Rodríguez, J.J.; Andrés, M.F.; Ibañez-Escribano, A.; Julio, L.F.; Burillo, J.; Bolás-Fernández, F.; González-Coloma, A. Selective nematocidal effects of essential oils from two cultivated Artemisia absinthium populations. Z. Nat. C J. Biosci. 2015, 70, 275–280. [Google Scholar] [CrossRef]
  6. Hentzschel, C.M.; Sakmann, A.; Leopold, C.S. Suitability of various excipients as carrier and coating materials for liquisolid compacts. Drug Dev. Ind. Pharm. 2011, 37, 1200–1207. [Google Scholar] [CrossRef]
  7. Gumaste, S.G.; Pawlak, S.A.; Dalrymple, D.M.; Nider, C.J.; Trombetta, L.D.; Serajuddin, A.T.M. Development of solid SEDDS, IV: Effect of adsorbed lipid and surfactant on tableting properties and surface structures of different silicates. Pharm. Res. 2013, 30, 3170–3185. [Google Scholar] [CrossRef] [Green Version]
  8. Mandić, J.; Zvonar Pobirk, A.; Vrečer, F.; Gašperlin, M. Overview of solidification techniques for self-emulsifying drug delivery systems from industrial perspective. Int. J. Pharm. 2017, 533, 335–345. [Google Scholar] [CrossRef]
  9. Das, S.; Ng, W.K.; Tan, R.B.H. Are nanostructured lipid carriers (NLCs) better than solid lipid nanoparticles (SLNs): Development, characterizations and comparative evaluations of clotrimazole-loaded SLNs and NLCs? Eur. J. Pharm. Sci. 2012, 47, 139–151. [Google Scholar] [CrossRef]
  10. Giannini, G.; Santaniello, M. A Versatile and stable mixture of fish oil and resveratrol in a powder formulation. Nutr. Food Technol. Open Access 2016, 2. [Google Scholar] [CrossRef]
  11. Tran, Q.T.; Vu, T.H.M.; Tran, V.T. Preparation of 200 mg fenofibrate hard capsule with high dissolution profile with microparticle entrapped micelles technology. Mahidol. Univ. J. Pharm. Sci. 2017, 44, 50–57. [Google Scholar] [CrossRef]
  12. Choudhari, Y.; Reddy, U.; Monsuur, F.; Pauly, T.; Hoefer, H.; McCarthy, W. Comparative evaluation of porous silica based carriers for lipids and liquid drug formulations. Mesoporous Biomater. 2014, 1, 61–74. [Google Scholar] [CrossRef]
  13. Lunter, D.J. Evaluation of mesoporous silica particles as drug carriers in hydrogels. Pharm. Dev. Technol. 2018, 23, 826–831. [Google Scholar] [CrossRef] [PubMed]
  14. Madhav, K.V.; Kishan, V. Self microemulsifying particles of loratadine for improved oral bioavailability: Preparation, characterization and in vivo evaluation. J. Pharm. Investig. 2018, 48, 497–508. [Google Scholar] [CrossRef]
  15. Waters, L.J.; Hanrahan, J.P.; Tobin, J.M.; Finch, C.V.; Parkes, G.M.B.; Ahmad, S.A.; Mohammad, F.; Saleem, M. Enhancing the dissolution of phenylbutazone using Syloid® based mesoporous silicas for oral equine applications. J. Pharm. Anal. 2018, 8, 181–186. [Google Scholar] [CrossRef] [PubMed]
  16. Pharmaceutical on-line Journal—Application Note; Multifunctional Excipients for the Pharmaceutical Industry. Available online: https://www.pharmaceuticalonline.com/doc/multifunctional-excipients-for-the-pharmaceutical-industry-0001 (accessed on 13 September 2020).
  17. Chen, Y.; Wang, J.; Flanagan, D.R. Particle, powder and compact characterization. In Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice; Academic Press: Cambridge, MA, USA, 2016; pp. 271–296. [Google Scholar]
  18. Gumaste, S.G.; Dalrymple, D.M.; Serajuddin, A.T.M. Development of solid SEDDS, V: Compaction and drug release properties of tablets prepared by adsorbing lipid-based formulations onto Neusilin® US2. Pharm. Res. 2013, 30, 3186–3199. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Martinello, T.; Kaneko, T.M.; Velasco, M.V.R.; Taqueda, M.E.S.; Consiglieri, V.O. Optimization of poorly compactable drug tablets manufactured by direct compression using the mixture experimental design. Int. J. Pharm. 2006, 322, 87–95. [Google Scholar] [CrossRef]
  20. Swarbrick, J. Encyclopedia of Pharmaceutical Technology; Informa Healthcare: London, UK, 2007; ISBN 978-0-8493-9391-4. [Google Scholar]
  21. Rojas, J.J.; Aristizabal, J.; Henao, M. Screening of several excipients for direct compression of tablets: A new perspective based on functional properties. Rev. Ciênc. Farm. Básica E Appl. 2013, 34, 17–23. [Google Scholar]
  22. Mangal, S.; Meiser, F.; Morton, D.; Larson, I. Particle Engineering of excipients for direct compression: Understanding the role of material properties. Curr. Drug Metab. 2015, 21, 5877–5889. [Google Scholar] [CrossRef]
  23. Vialpando, M.; Aerts, A.; Persoons, J.; Martens, J.; Mooter, G.V.D. Evaluation of ordered mesoporous silica as a carrier for poorly soluble drugs: Influence of pressure on the structure and drug release. J. Pharm. Sci. 2011, 100, 3411–3420. [Google Scholar] [CrossRef]
  24. Mattsson, S.; Nyström, C. Evaluation of critical binder properties affecting the compactibility of binary mixtures. Drug Dev. Ind. Pharm. 2001, 27, 181–194. [Google Scholar] [CrossRef] [PubMed]
  25. Lin, Y.-H.; Tsai, M.-J.; Fang, Y.-P.; Fu, Y.-S.; Huang, Y.-B.; Wu, P.-C. Microemulsion formulation design and evaluation for hydrophobic compound: Catechin topical application. Colloids Surf. B Biointerfaces 2017, 161, 121–128. [Google Scholar] [CrossRef] [PubMed]
  26. Cao, M.; Ren, L.; Chen, G. Formulation optimization and ex vivo and in vivo evaluation of celecoxib microemulsion-based gel for transdermal delivery. AAPS PharmSciTech 2017, 18, 1960–1971. [Google Scholar] [CrossRef] [PubMed]
  27. Jagdale, S.; Chaudhari, B. Optimization of microemulsion based transdermal gel of triamcinolone. Recent Patents Anti-Infect. Drug Disc. 2017, 12, 61–78. [Google Scholar] [CrossRef]
  28. Ansari, K.A.; Pagar, K.P.; Anwar, S.; Vavia, P.R.; Ansari, K.A.; Pagar, K.P.; Anwar, S.; Vavia, P.R. Design and optimization of self-microemulsifying drug delivery system (SMEDDS) of felodipine for chronotherapeutic application. Braz. J. Pharm. Sci. 2014, 50, 203–212. [Google Scholar] [CrossRef] [Green Version]
  29. Dalvadi, H.; Patel, N.; Parmar, K. Systematic development of design of experiments (DoE) optimised self-microemulsifying drug delivery system of Zotepine. J. Microencapsul. 2017, 34, 308–318. [Google Scholar] [CrossRef]
  30. Valicherla, G.R.; Dave, K.M.; Syed, A.A.; Riyazuddin, M.; Gupta, A.P.; Singh, A.; Wahajuddin; Mitra, K.; Datta, D.; Gayen, J.R. Formulation optimization of Docetaxel loaded self-emulsifying drug delivery system to enhance bioavailability and anti-tumor activity. Sci. Rep. 2016, 6, 26895. [Google Scholar] [CrossRef]
  31. Ćurić, A.; Reul, R.; Möschwitzer, J.; Fricker, G. Formulation optimization of itraconazole loaded PEGylated liposomes for parenteral administration by using design of experiments. Int. J. Pharm. 2013, 448, 189–197. [Google Scholar] [CrossRef]
  32. Mura, P.; Capasso, G.; Maestrelli, F.; Furlanetto, S. Optimization of formulation variables of benzocaine liposomes using experimental design. J. Liposome Res. 2008, 18, 113–125. [Google Scholar] [CrossRef]
  33. Tibalinda, P.; Sempombe, J.; Shedafa, R.; Masota, N.; Pius, D.; Temu, M.; Kaale, E. Formulation development and optimization of Lamivudine 300 mg and Tenofovir Disoproxil Fumarate (TDF) 300 mg FDC tablets by D-optimal mixture design. Heliyon 2016, 2, e00207. [Google Scholar] [CrossRef] [Green Version]
  34. Yeom, D.W.; Chae, B.R.; Kim, J.H.; Chae, J.S.; Shin, D.J.; Kim, C.H.; Kim, S.R.; Choi, J.H.; Song, S.H.; Oh, D.; et al. Solid formulation of a supersaturable self-microemulsifying drug delivery system for valsartan with improved dissolution and bioavailability. Oncotarget 2017, 8, 94297–94316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Mohamad Zen, N.I.; Abd Gani, S.S.; Shamsudin, R.; Fard Masoumi, H.R. The use of D-optimal mixture design in optimizing development of okara tablet formulation as a dietary supplement. Sci. World J. 2015, 2015, 684319. [Google Scholar] [CrossRef] [PubMed]
  36. Malakar, J.; Nayak, A.K.; Goswami, S. Use of response surface methodology in the formulation and optimization of bisoprolol fumarate matrix tablets for sustained drug release. ISRN Pharm. 2012, 2012. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Bolourtchian, N.; Hadidi, N.; Foroutan, S.M.; Shafaghi, B. Formulation and optimization of captopril sublingual tablet using D-optimal design. Iran. J. Pharm. Res. 2008, 7, 259–267. [Google Scholar]
  38. Maltais, M.; Vargas, R.; DiPaolo, T. Development of a new formulation for direct compression of a natural product. J. Pharm. Technol. Drug Res. 2015, 4, 2. [Google Scholar] [CrossRef]
  39. Myers, R.H.; Montgomery, D.C.; Anderson-Cook, C.M. Wiley series in probability and statistics. In Response Surface Methodology: Process and Product Optimization Using Designed Experiments, 4th ed.; Wiley: Hoboken, NJ, USA, 2016; ISBN 978-1-118-91601-8. [Google Scholar]
  40. He, S.; Ren, X.; Lu, Y.; Zhang, Y.; Wang, Y.; Sun, L. Microemulsification of clove essential oil improves its in vitro and in vivo control of Penicillium digitatum. Food Control. 2016, 65, 106–111. [Google Scholar] [CrossRef]
  41. Zhao, Y.; Wang, C.; Chow, A.H.L.; Ren, K.; Gong, T.; Zhang, Z.; Zheng, Y. Self-nanoemulsifying drug delivery system (SNEDDS) for oral delivery of Zedoary essential oil: Formulation and bioavailability studies. Int. J. Pharm. 2010, 383, 170–177. [Google Scholar] [CrossRef]
  42. United States Pharmacopeia and National Formulary (USP 38–NF 33); United States Pharmacopeial Convention: Rockville, MD, USA, 2016.
  43. Fell, J.T.; Newton, J.M. Determination of tablet strength by the diametral-compression test. J. Pharm. Sci. 1970, 59, 688–691. [Google Scholar] [CrossRef]
  44. Rowe, R.C. Handbook of Pharmaceutical Excipients, 6th ed.; Pharmaceutical Press: London, UK, 2009; ISBN 978-0-85369-792-3. [Google Scholar]
  45. Bühler, V. Soluble polyvinylpyrrolidone (Povidone). In Polyvinylpyrrolidone Excipients for Pharmaceuticals: Povidone, Crospovidone and Copovidone; Springer: Berlin, Germany, 2010; pp. 5–125. [Google Scholar]
  46. Said, M.; Elsayed, I.; Aboelwafa, A.A.; Elshafeey, A.H. Transdermal agomelatine microemulsion gel: Pyramidal screening, statistical optimization and in vivo bioavailability. Drug Deliv. 2017, 24, 1159–1169. [Google Scholar] [CrossRef] [Green Version]
  47. Huang, Y.-B.; Tsai, Y.-H.; Yang, W.-C.; Chang, J.-S.; Wu, P.-C.; Takayama, K. Once-daily propranolol extended-release tablet dosage form: Formulation design and in vitro/in vivo investigation. Eur. J. Pharm. Biopharm. 2004, 58, 607–614. [Google Scholar] [CrossRef]
  48. Dean, A.; Morris, M.; Stufken, J.; Bingham, D. Handbook of Design and Analysis of Experiments; CRC Press: Boca Raton, FL, USA, 2015. [Google Scholar]
  49. Muzíková, J. Effect of magnesium stearate on the tensile strength of tablets made with the binder Prosolv SMCC 90. Ceska Slov. Farm. Cas. Ceske Farm. Spol. Slov. Farm. Spol. 2002, 51, 41–43. [Google Scholar]
  50. Jarosz, P.J.; Parrott, E.L. Effect of lubricants on tensile strengths of tablets. Drug Dev. Ind. Pharm. 1984, 10, 259–273. [Google Scholar] [CrossRef]
  51. Sheikh-salem, M.; Alkaysi, H.; Fell, J.T. The tensile strength of tablets of binary mixtures lubricated with magnesium stearate. Drug Dev. Ind. Pharm. 1988, 14, 895–903. [Google Scholar] [CrossRef]
  52. Muzíková, J.; Louzenska, M.; Pekarek, T. A study of compression process and properties of tablets with microcrystalline cellulose and colloidal silicon dioxide. Acta Poliniae Pharm. 2016, 73, 1259–1265. [Google Scholar]
  53. Pingali, K.; Mendez, R.; Lewis, D.; Michniak-Kohn, B.; Cuitino, A.; Muzzio, F. Mixing order of glidant and lubricant—Influence on powder and tablet properties. Int. J. Pharm. 2011, 409, 269–277. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Agarwal, V.; Siddiqui, A.; Ali, H.; Nazzal, S. Dissolution and powder flow characterization of solid self-emulsified drug delivery system (SEDDS). Int. J. Pharm. 2009, 366, 44–52. [Google Scholar] [CrossRef]
  55. Chen, L.; Ding, X.; He, Z.; Huang, Z.; Kunnath, K.T.; Zheng, K.; Davé, R.N. Surface engineered excipients: I. improved functional properties of fine grade microcrystalline cellulose. Int. J. Pharm. 2018, 536, 127–137. [Google Scholar] [CrossRef]
  56. Ferrero, C.; Muñoz, N.; Velasco, M.V.; Muñoz-Ruiz, A.; Jiménez-Castellanos, R. Disintegrating efficiency of croscarmellose sodium in a direct compression formulation. Int. J. Pharm. 1997, 147, 11–21. [Google Scholar] [CrossRef]
  57. Wang, Z.; Sun, J.; Wang, Y.; Liu, X.; Liu, Y.; Fu, Q.; Meng, P.; He, Z. Solid self-emulsifying nitrendipine pellets: Preparation and in vitro/in vivo evaluation. Int. J. Pharm. 2010, 383, 1–6. [Google Scholar] [CrossRef]
  58. Mirani, A.G.; Patankar, S.P.; Borole, V.S.; Pawar, A.S.; Kadam, V.J. Direct compression high functionality excipient using coprocessing technique: A brief review. Curr. Drug Deliv. 2011, 8, 426–435. [Google Scholar] [CrossRef]
  59. Sun, C.C.; Hou, H.; Gao, P.; Ma, C.; Medina, C.; Alvarez, F.J.; Hou, H.; Gao, P. Development of a high drug load tablet formulation based on assessment of powder manufacturability: Moving towards quality by design. J. Pharm. Sci. 2009, 98, 239–247. [Google Scholar] [CrossRef] [PubMed]
  60. Kachrimanis, K.; Nikolakakis, I.; Malamataris, S. Tensile strength and disintegration of tableted silicified microcrystalline cellulose: Influences of interparticle bonding. J. Pharm. Sci. 2003, 92, 1489–1501. [Google Scholar] [CrossRef] [PubMed]
  61. Tye, C.K.; Sun, C.C.; Amidon, G.E. Evaluation of the effects of tableting speed on the relationships between compaction pressure, tablet tensile strength, and tablet solid fraction. J. Pharm. Sci. 2005, 94, 465–472. [Google Scholar] [CrossRef] [PubMed]
  62. Diarra, H.; Mazel, V.; Busignies, V.; Tchoreloff, P. Investigating the effect of tablet thickness and punch curvature on density distribution using finite elements method. Int. J. Pharm. 2015, 493, 121–128. [Google Scholar] [CrossRef] [PubMed]
  63. World Health Organization. Revision of Monograph on Tablets. Final Text for Addition to The International Pharmacopoeia; WHO: Geneva, Switzerland, 2011. [Google Scholar]
  64. Al-Gousous, J.; Langguth, P. Oral solid dosage form disintegration testing—The forgotten test. J. Pharm. Sci. 2015, 104, 2664–2675. [Google Scholar] [CrossRef] [Green Version]
Pharmaceutics 12 00873 g001 550
Figure 1. Appearance of the Syloid® XDP:ME (1:1.5) system (A) at 40× (B) and 100× (C).
Figure 1. Appearance of the Syloid® XDP:ME (1:1.5) system (A) at 40× (B) and 100× (C).
Pharmaceutics 12 00873 g001
Pharmaceutics 12 00873 g002 550
Figure 2. Tensile strength using several binders (A) at different compression forces (B). Note: average results ± 95% Confidence Interval (CI) (n = 3). Abbreviatures: PVP: polyvinylpyrrolidone.
Figure 2. Tensile strength using several binders (A) at different compression forces (B). Note: average results ± 95% Confidence Interval (CI) (n = 3). Abbreviatures: PVP: polyvinylpyrrolidone.
Pharmaceutics 12 00873 g002
Pharmaceutics 12 00873 g003 550
Figure 3. Comparison of predicted and actual values: tensile strength (A) and disintegration time (B). Note: average results ± 95% CI (n = 3).
Figure 3. Comparison of predicted and actual values: tensile strength (A) and disintegration time (B). Note: average results ± 95% CI (n = 3).
Pharmaceutics 12 00873 g003
Table
Table 1. Design constraints for each component.
Table 1. Design constraints for each component.
ComponentMinimum (% w/w)Maximum (% w/w)
Syloid® XDP:ME (1:1.5)3260
MCC2040
PVP020
CCMNa06
Syloid® 24401
MgSt0.51
Abbreviatures: ME: microemulsion; MCC: microcrystalline cellulose; CCMNa: croscarmellose sodium; MgSt: magnesium stearate; PVP: polyvinylpyrrolidone. References: Rowe R.C., 2009 [43].
Table
Table 2. Flow and tableting properties of the silica material.
Table 2. Flow and tableting properties of the silica material.
ParameterSyloid® XDPSyloid® XDP:ME (1:1.5)
Bulk density (g/mL)0.281 ± 0.0000.730 ± 0.029
Tapped density (g/mL)0.319 ± 0.0000.882 ± 0.028
Compressibility index12.000 ± 0.00017.216 ± 3.291
Hausner ratio1.136 ± 0.0001.210 ± 0.049
Angle of repose26.589 ± 1.14221.608 ± 2.636
Note: average results ± standard deviation (n = 3).
Table
Table 3. Composition of the 16 experiments.
Table 3. Composition of the 16 experiments.
ExpSyloid® XDP:ME (1:1.5)
(% w/w)		MCC
(% w/w)		PVP
(% w/w)		CCMNa
(% w/w)		Syloid® 244
(% w/w)		MgSt
(% w/w)
142.8929.7619.415.941.001.00
256.5340.000.002.190.730.56
352.2323.0920.003.410.660.62
442.6939.9015.670.000.750.99
552.2323.0920.003.410.660.62
636.1639.6716.696.000.660.82
746.9940.005.106.000.911.00
853.9229.6014.490.000.991.00
955.5530.945.526.001.001.00
1060.0024.0311.743.290.080.86
1148.5835.8911.233.030.520.75
1260.0024.0311.743.300.080.86
1348.2530.2916.103.380.990.99
1442.6939.9015.670.000.750.99
1556.5240.000.002.190.730.56
1636.1639.6716.706.000.660.82
Abbreviations: CCMNa: croscarmellose sodium, Exp: experiment, MCC: microcrystalline cellulose, ME: microemulsion, MgSt: magnesium stearate.
Table
Table 4. Flow properties and responses of the experiments in the D-optimal mixture design.
Table 4. Flow properties and responses of the experiments in the D-optimal mixture design.
Exp.Bulk DensityTapped DensityComp. IndexHausner RatioFlow *,†Angle of ReposeFlow *,‡
10.44 ± 0.000.48 ± 0.009.78 ± 0.001.11 ± 0.00Excellent16 ± 2Excellent
20.51 ± 0.000.57 ± 0.0011.11 ± 0.001.13 ± 0.00Good20 ± 1Excellent
30.42 ± 0.010.50 ± 0.0215.81 ± 2.981.19 ± 0.04Fair23 ± 3Excellent
40.39 ± 0.020.44 ± 0.0111.00 ± 2.801.12 ± 0.04Good16 ± 1Excellent
50.42 ± 0.010.44 ± 0.145.50 ± 2.981.06 ± 0.03Excellent16 ± 6Excellent
60.36 ± 0.000.45 ± 0.0021.05 ± 0.001.28 ± 0.00Passable24 ± 3Excellent
70.45 ± 0.000.50 ± 0.0011.11 ± 0.001.13 ± 0.00Good7 ± 4Excellent
80.33 ± 0.000.40 ± 0.0016.67 ± 0.001.20 ± 0.00Fair12 ± 5Excellent
90.40 ± 0.000.47 ± 0.0015.00 ± 0.001.18 ± 0.00Good25 ± 6Excellent
100.37 ± 0.000.45 ± 0.0018.18 ± 0.001.22 ± 0.00Fair24 ± 1Excellent
110.41 ± 0.000.45 ± 0.007.69 ± 0.001.08 ± 0.00Excellent25 ± 2Excellent
120.42 ± 0.000.50 ± 0.0016.60 ± 0.001.20 ± 0.00Fair24 ± 2Excellent
130.42 ± 0.000.48 ± 0.0212.28 ± 3.041.14 ± 0.04Good22 ± 1Excellent
140.30 ± 0.000.38 ± 0.0020.46 ± 0.001.26 ± 0.00Passable25 ± 3Excellent
150.50 ± 0.000.57 ± 0.0012.50 ± 0.001.14 ± 0.00Good19 ± 0Excellent
160.31 ± 0.000.35 ± 0.0011.54 ± 0.001.13 ± 0.00Good21 ± 2Excellent
Notes: average results ± standard deviation (n = 3) * Classification according to the USP 38 [41]. † According to the Comp. Index and Hausner ratio results. ‡ According to the results of the angle of repose. Abbreviations: Exp.: experiment.
Table
Table 5. Flow properties and responses of the experiments in the D-optimal mixture design.
Table 5. Flow properties and responses of the experiments in the D-optimal mixture design.
ExperimentTensile Strength (MPa)Disintegration Time (min)
Minimum ValueMaximum ValueAverage ± SD
11.8212.2912.052 ± 0.1945.600
20.3580.4200.388 ± 0.0230.300
32.2573.1662.703 ± 0.4015.550
42.0842.3792.230 ± 0.10314.000
52.0243.0162.510 ± 0.4469.217
62.5702.7362.652 ± 0.0306.400
70.7940.9770.884 ± 0.0741.500
81.9082.4972.197 ± 0.2519.417
90.0000.0000.000 ± 0.0000.000
102.3613.0452.697 ± 0.2885.667
110.7760.7790.777 ± 0.0000.000
120.1330.1370.136 ± 0.0005.776
131.9533.2052.567 ± 0.5747.383
142.0982.4872.289 ± 0.1490.383
150.4120.6300.519 ± 0.0990.200
162.2632.9562.603 ± 0.2956.958
Notes: Results with a 0.000 value indicate that the experiment could not be measured for that variable.
Table
Table 6. Results of the linear model based on tensile strength responses.
Table 6. Results of the linear model based on tensile strength responses.
ParameterSum of SquaresDegrees of FreedomMean SquareF-Valuep-Value
Tensile Strength (MPa)
Model8.4351.6919.580.0001
Linear mixture8.4351.6919.580.0001
Residual0.7890.09--
Lack of fit0.7550.1519.860.0063
Pure error0.0340.01--
Corrected Sum of Squares9.2114---
Disintegration Time (min)
Model85.09517.0212.060.0044
Linear mixture85.09517.0212.060.0044
Residual8.4761.41--
Lack of fit1.5930.530.2300.8700
Pure error6.8832.29--
Corrected Sum of Squares93.5611---

Share and Cite

MDPI and ACS Style

Perez-Roman, I.; Kiekens, F.; Cordoba-Diaz, D.; Garcia-Rodriguez, J.J.; Cordoba-Diaz, M. Development of a Solid Formulation Containing a Microemulsion of a Novel Artemisia Extract with Nematocidal Activity for Oral Administration. Pharmaceutics 2020, 12, 873. https://doi.org/10.3390/pharmaceutics12090873

AMA Style

Perez-Roman I, Kiekens F, Cordoba-Diaz D, Garcia-Rodriguez JJ, Cordoba-Diaz M. Development of a Solid Formulation Containing a Microemulsion of a Novel Artemisia Extract with Nematocidal Activity for Oral Administration. Pharmaceutics. 2020; 12(9):873. https://doi.org/10.3390/pharmaceutics12090873

Chicago/Turabian Style

Perez-Roman, Ines, Filip Kiekens, Damian Cordoba-Diaz, Juan Jose Garcia-Rodriguez, and Manuel Cordoba-Diaz. 2020. "Development of a Solid Formulation Containing a Microemulsion of a Novel Artemisia Extract with Nematocidal Activity for Oral Administration" Pharmaceutics 12, no. 9: 873. https://doi.org/10.3390/pharmaceutics12090873

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop