Feasability of a new process to produce fast disintegrating pellets as novel multiparticulate dosage form for pediatric use

International Journal of Pharmaceutics 496 (2015) 842–849

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International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

Feasability of a new process to produce fast disintegrating pellets as novel multiparticulate dosage form for pediatric use Thanh Huong Hoang Thia , Siham Lhafidia , Simone Pinto Carneirob , Marie-Pierre Flamenta,c,* a

Univ. Lille, Inserm, CHU Lille, U 1008—Controlled Drug Delivery Systems and Biomaterials, F-5900 Lille, France Laboratório de Desenvolvimento Galênico, Nanobiotecnologia e Tecnologia Farmacêutica, Universidade Federal de Ouro Preto, Morro do Cruzeiro, 35400-000 Ouro Preto, Brazil c Univ. Lille, Faculté d’Ingénierie et Management de la Santé (ILIS), 42 rue Ambroise Paré, F-59120 Loos, France b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 3 July 2015 Received in revised form 17 September 2015 Accepted 19 September 2015 Available online 25 September 2015

Novel orally disintegrating system based on multiparticulate form was developed, offering an alternative to encounter major issues in the design of dosage form for pediatric patients, i.e., the difficulty in swallowing large solid dosage form (tablet or capsule), and the requirement to cover a broad range of doses for different age groups. Microcrystalline cellulose-based pellets containing acetaminophen were prepared via extrusion/spheronization followed by freeze-drying. The in vitro disintegration behavior of these pellets was quantitatively measured with a texture analyzer. Mercury intrusion and gas adsorption techniques, scanning electron microscopy of pellet surface and cross-section were performed in order to characterize their internal porous structure. Pellets characteristics such as size distribution, sphericity, friability and drug release were also determined. The developing process was able to produce pellets containing high drug loading (25, 50 and up to 75%, w/w) with good sphericity (aspect ratio
1) and low friability. The pellets exhibited an instantaneous disintegration upon contact with water, which was indicated by two parameters: the disintegration onset was approximating to 0, and the disintegration time less than 5 s. The fast disintegration behavior is correlated with the pellet internal structure characterized by a capillary network with pore diameter varying from 0.1 to 10 mm. Such a structure not only ensured a rapid disintegration but it also offers to freeze-dried pellets adequate mechanical properties in comparison with conventional freeze-dried forms. Due to pellet disintegration, fast dissolution of acetaminophen was achieved, i.e., more than 90% of drug released within 15 min. This novel multiparticulate system offers novel age-appropriate dosage form for pediatric population owing to their facility of administration (fast disintegration) and dosing flexibility (divided and reduced-size solid form). ã 2015 Elsevier B.V. All rights reserved.

Keywords: Pediatric dosage form Fast disintegration Extrusion/spheronization Freeze-drying

1. Introduction Due to the lack of approved drugs and appropriate formulations, children represent the most vulnerable patients. The World Health Organization (WHO) estimates that
50% of the medicines prescribed for children are not commercially available in pediatric form (Nahata and Allen, 2008). To ensure a simple and safe drug administration, a dosage form intended for pediatric use requires a particular design because of specific characteristics of this population. Main challenges in the design of such dosage form

* Corresponding author at: Université Lille Nord de France, Faculté d'Ingénierie et Management de la Santé (ILIS), 42 rue Ambroise Paré, 59120 Loos, France. Fax: +33 3 20 62 37 38. E-mail address: marie-pierre.fl[email protected] (M.-P. Flament). http://dx.doi.org/10.1016/j.ijpharm.2015.09.049 0378-5173/ ã 2015 Elsevier B.V. All rights reserved.

include how to encounter the dosing issues and to facilitate the medicine administration (Breitkreutz and Boos, 2007; Nunn and Williams, 2005; Schirm et al., 2003). Indeed, pediatric patients constitute a heterogeneous population of widely varying ages that is going through periods of rapid growth, maturation and development (Bowles et al., 2010; Dotta et al., 2011). The magnitude of dose required must be consequently adapted to this change and usually related to children's body weight. There are also significant changes in the ability to handle different dosage forms. Age-adapted dosage forms are essential for younger age groups. Children under six years old have difficulties in swallowing conventional solid dosage forms such as tablets and capsules because of their size and hardness. Liquid dosage forms often prescribed are easier to administer but may be limited in use due to their stability, packaging, inaccurate dosing and cost (Sosnik et al.,

T.H. Hoang Thi et al. / International Journal of Pharmaceutics 496 (2015) 842–849

2012). In a report of the informal expert meeting on dosage forms of medicines for children, WHO recommended that small sized solid forms and/or orally disintegrating solid forms should be favored (WHO, 2008). Pellets are small spherical solid dosage form having a mean size between 0.5 and 2 mm (in diameter). Pellets have been readily investigated as controlled drug delivery system because they offer advantages over single-unit dosage form, such as less irritation of the gastrointestinal tract, lowered risk of side effects due to dose dumping, reproducible drug blood levels (Wang et al., 2015; Qi et al., 2015; Hung et al., 2015; De Barros et al., 2015; Vervaet et al., 1995). As multiparticulate dosage form, pellets are particularly interesting in the development of medicines for children. Since each individual unit contains a small amount of drug, dose adjustment can be accurately achieved by means of dosing device e.g., particulate counting devices or volume/weight measuring devices. Flexible dosing dosage form allows therefore covering a broad range of doses for different age groups and especially for children suffering chronic diseases. The most commonly used pelletization technique is extrusion/spheronization because it offers a number of technological advantages: ease of operation, high throughput process, pellets produced having narrow size distribution and low friability, ability of high drug loading, etc. (Vervaet et al., 1995). Microcrystalline cellulose is considered as standard pelletization aid in extrusion/spheronization because it provides the most suitable plasticity and cohesiveness to the wet mass prior to extrusion and spheronization (Law and Deasy, 1998; Mastropietro and Omidian, 2013; Thommes and Kleinebudde, 2006). However, microcrystalline cellulose based pellets have a prolonged disintegration time (Kleinebudde, 1994; Zimm et al., 1996). Various approaches have been evaluated to overcome this limitation e.g., partial or total substitution of microcrystalline cellulose with soluble diluents (Fielden et al., 1993; Ku et al., 1993; Sousa et al., 2002; Baert et al., 1992; Goyanes et al., 2010), incorporation of superdisintegrants (Souto et al., 2005; Schröder and Kleinebudde, 1995; Goyanes et al., 2011, 2013). The production of orally disintegrating pellets constitutes therefore a great challenge. The European Pharmacopoeia describes orally disintegrating tablets as uncoated tablets intended to be placed in the mouth where they disperse rapidly i.e., within 3 min before being swallowed. FDA defines orally disintegrating tablet as a solid dosage form which disintegrates rapidly within a matter of seconds when placed upon a tongue. Hence, this kind of dosage form is claimed to be the most convenient mode of medicine administration for pediatric population and other patients with dysphagia. It can disintegrate and/or dissolve spontaneously in the oral cavity, resulting in a suspension or solution that can be easily swallowed. Also, fast disintegrating systems have all advantages of solid dosage forms e.g., good stability, accurate dosing, easy handling by patients and advantages of liquid formulations e.g., easy administration, no risk of suffocation due to physical obstruction (Habib et al., 2000; Saigal et al., 2008). Different technologies have been investigated to develop orally disintegrating tablets with a particular shift to freeze-drying (Saigal et al., 2008; Parkash et al., 2011; AlHusban et al., 2010). Indeed, tablets prepared by freeze-drying technique possess highly porous structure that enhances the water adsorption and hence facilitates rapid disintegration (Schwegman et al., 2005; Liu, 2006). However, due to a very large pore size (>10 mm), freeze-dried products are extremely brittle and difficult to handle (Lafon, 1986; Kearney and Wong, 1997; Green and Kearney, 1999; Corveleyn and Remon, 1997). Achieving a better mechanical strength that is suitable for packaging and handling is therefore a critical factor during the development of orally disintegrating systems. The association of extrusion-spheronization and freeze-drying was also applied to

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pellets (Balaxi et al., 2010; Lutchman et al., 2005). Pellets of high porosity could be obtained by varying the operating conditions. Since porosity and pore size distribution are known to affect drug release, these findings may be useful in the delivery of drugs (Balaxi et al., 2010). High porosity could also improve the penetration of water in the pellets and then the disintegration of pellets which is important for orodispersible solid dosage forms. The aim of this study is to evaluate the feasibility of combining these two well-established technologies i.e., extrusion/spheronization and freeze-drying in order to produce pellets that have fast disintegration and better mechanical strength as a novel dosage form for pediatric use. An instantaneous disintegration of the pellets while maintaining their mechanical strength would be interesting for paediatric orodispersible solid dosage forms. Acetaminophen was used as a model drug. 2. Materials and methods 2.1. Materials Pulverized acetaminophen from Cooper (Melun, France); microcrystalline cellulose Avicel PH 101 from FMC (Cork, Ireland); acetonitrile HPLC grade (99.9%), trimethylamine HPLC grade (99.9%) and monobasic potassium phosphate crystalline (KH2PO4) from Fischer Chemical (Leicestershire, UK); phosphoric acid powder analytical grade (99.9%) from Merck (Darmstadt, Germany). All materials were used as received. Particle size distribution of acetaminophen and microcrystalline cellulose (MCC) were determined by Mastersizer S (Malvern Instrument, Orsay, France) and were presented in Table 1. 2.2. Methods 2.2.1. Pellet manufacturing process Fig. 1 illustrates the manufacturing process of the pellets developped. 100 g of microcrystalline cellulose or blends of microcrystalline cellulose and acetaminophen (25, 50 and 75%, w/w) previously mixed for 10 min in a Turbula mixer (Bachofen Maschinenfabrik, Basel, Switzerland) was granulated by means of a planetary mixer fitted with a K-beater attachment (Kenwood, Croydon, UK). Demineralized water was gradually added into the powder blend during 1 min and the mixer was stirring at minimum speed for further 5 min. Any caked paste was regularly removed from the wall of the mixing bowl and the K-mixing arm to ensure uniform water distribution through the wet mass. The extrusion was performed on an Alexanderwerk GA 65 cylinder extruder (Remscheid, Germany) equipped with two counter-rotating cylinders: the granulating cylinder is perforated (1-mm diameter hole) and the other cylinder is solid. The rotation speed was 96 rpm and the wet mass was introduced between the two cylinders by gravity. The extrudates were spheronized for 1 min in a Caleva 15 spheronizer (Dorset, England) rotating at 765 rpm. Pellets were subsequently dried in an Epsilon 2–4 freeze-dryer (Martin Christ, Osterode am Harz, Germany). The freeze-drying included a freezing at 45  C for 2 h, a primary drying (0.014 mbar, 10  C shelf temperature, for 10 h) and a secondary drying (0.0014 mbar, 20  C shelf temperature, for 10 h). Pellets were also dried by oven at Table 1 Particle size distribution of raw materials (in micrometers).

Acetaminophen Avicel PH 101

D(4, 3)

D(v, 0.1)

D(v, 0.5)

D(v, 0.9)

11.6 62.3

1.9 14.5

7.2 53.6

27.9 122.8

D(4, 3) is the volume mean diameter; D(v, 0.5) is the size of particle at which 50% of the sample is smaller and 50% is larger than this size; D(v, 0.1) and D(v, 0.9) the size of particle for which 10% and 90% of the sample is below this size, respectively.

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API

MCC DRY MIXING

Water

Powder blend

2.2.2.4. Friability. A sample of pellets (5 g) was placed into a 30-mL glass container together with 5 g of stainless steel beads and was subjected to oscillatory movements by means of a Turbula mixer (Bachofen Maschinenfabrik, Basel, Switzerland) rotating at 27 rpm for 5 min. Afterward the fines were removed by sieving through a 355-mm mesh, the pellet friability was calculated by the percentage of the pellet weight loss.

WET MASSING Wet mass

EXTRUSION Extrudates

SPHERONISATION Wet pellets

FREEZE-DRYING Final pellets Fig. 1. Pellet manufacturing process.

60  C overnight for comparison. Dried pellets were kept at 20  C from humidity. 2.2.2. Pellet characterization 2.2.2.1. Moisture content. A sample of pellets (3 g) was weighed before and after heating up to 105  C for 30 min by using an infrared moisture analyzer (Mettler Toledo SA, Viroflay, France). The moisture content was calculated by the percentage of the pellet weight loss. 2.2.2.2. Sieve analysis. 100 g of pellets were sieved through a nest of sieves of aperture sizes of 2000, 1676, 1250, 1000, 710 and 500 mm. Sieving was performed on a mechanical sieve shaker (Retsch, Haan, Germany) for 10 min. Pellet size distribution was presented as the percentage of the total pellet weight for each size fraction. The 1000–1250 mm sieve fraction was used for further tests described below. 2.2.2.3. Image analysis. Pellet morphology was determined individually using a Nikon SMZ-800 stereo-microscope (Melville, US) equipped with a camera AxioCam Icc1. The images were then analyzed by AxioVision software (Carl Zeiss, Jena, Germany). The measurement was carried out on 50 pellets to determine the aspect ratio that is defined as the ratio of the longest Feret diameter and its perpendicular diameter. Aspect ratio describes the pellet sphericity and expected to be close to 1.

2.2.2.5. Determination of disintegration time by texture analyzer. The disintegration time was determined in vitro using a TA.XT Plus texture analyzer (Stable Micro System, Surrey, UK) according to the method described by Dor and Fix (2000) and ElArini and Clas (2002). The instrument was calibrated with a 1-kg load cell and was fitted with a stainless steel flat-bottomed cylindrical probe P/3 (3-mm diameter). The methodology consisted in attaching one pellet to the flat bottom of the probe that moves downward. Once the pellet was in contact with the disintegration medium and a trigger force of 10 g was detected, the probe was set to maintain constantly a compression force of 50 g onto the pellet for 60 s. To simulate the in vivo conditions, a very small volume of disintegration medium was used by adding 20 mL demineralized water onto a 1-cm2 piece of filter paper (Fig. 2a). The analysis was carried out at room temperature. The results were presented as the mean of 20 measurements. The distance–time profile generated characterizes the disintegration behavior of the pellet and typically has three distinct phases (Fig. 2b): (i) The initial phase represents the sample resistance to the compression force applied via the probe or may indicate a swelling behavior of the pellet (distance value positive), (ii) The descending phase corresponds to the disintegration process in which the probe distance decreases in search of the target force as the pellet starts to disintegrate, (iii) The curve represents a plateau as the disintegration process is complete. Based on the distance–time curve, the following parameters were determined: - Disintegration onset t1 is the projection on the time axis of the intercept between the maximum of the initial phase and the slope of the descending phase, - Disintegration endpoint (t2), also defined as disintegration time, is the projection on the time axis of the intercept between the slope of the descending phase and the plateau.

2.2.2.6. Dissolution test. The dissolution test was performed on the USP basket apparatus (Sotax, Allschwil, Switzerland). 500 mg of

Fig. 2. (a) Experimental setup for the determination of disintegration time using texture analyzer and (b) a typical distance–time profile characterized by three distinct phases from which the onset t1 and the endpoint t2 of disintegration process can be extrapolated.

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100

cumulative percent of pellet weight (%)

pellets was added into 900 mL demineralized water rotated at 100 rpm and at 37  C. 5-mL sample was withdrawn at predetermined time intervals and was analyzed for drug content by HPLC. The HPLC system was equipped with a ProStar 230 pump, a ProStar 410 auto-sampler, a ProStar 325 UV–vis detector (Varian Inc., Les Ulis, France). The separation was performed on a Synergi Hydro-RP column (4 mm, 250  4.6 mm i.d.) (Phenomenex Inc., Le Pecq, France). The column temperature was 30  C. The mobile phase was a mixture (16:84, v/v) of acetonitrile and an aqueous phosphate buffer containing 20 mM monobasic potassium phosphate, 0.2 mL/L trimethylamine and adjusted to pH 3.3 with 3N phosphoric acid solution. The flow rate was 1 mL/min and the injection volume was 15 mL. The effluent peak was monitored at 243 nm. Chromatographic data were acquired by Galaxie Software.

845

75

50

25

0 100

1000

10000

pellet size (µm)

2.2.2.7. Scanning electron microscopy. The surface and crosssection morphologies of pellet were examined using a Hitachi S47000 apparatus (Tokyo, Japan). Samples were previously covered with carbon using a sputter coater in a vacuum. 2.2.2.8. Porosimetry by mercury intrusion. The technique is based on measuring the volume of a non-wetting liquid (mercury) intruded into a porous solid as a function of the applied pressure. The pressure applied is in inverse proportional to the inner diameter of the pore aperture. In the case of cylindrical pores, the correlation between pore diameter and pressure is given by the Washburn equation: d¼

4  s Hg cosuHg P

where d is the pore diameter (m), s Hg is the surface tension of mercury (0.485 N/m), uHg is the contact angle of mercury on the sample (130 ), P is the applied pressure (Pa). The measurement was performed on a Micromeritics Autopore 9400 mercury porosimeter (Georgia, USA). Samples were placed under vacuum overnight to eliminate moisture and contaminants adsorbed before analysis. The applied pressure varied from 0.004 to 200 MPa which corresponds to pore diameter ranging from 250 to 0.006 mm. 2.2.2.9. Porosimetry by gas adsorption. The technique is based on the physical adsorption of a gas by a solid in which gas condensation within porous structure occurs as the applied pressure increases. The measurement was performed on a Micromeritics ASAP 2010 analyzer (Georgia, USA) using nitrogen as adsorbate gas. Samples were placed under vacuum overnight to eliminate moisture and contaminants adsorbed before analysis. The determination was carried out at the temperature of liquid nitrogen (77.4 K) in the range of relative pressure from 0.231 to 0.995. The volume pore size distribution was calculated based on the Barret–Joyner–Halenda (BJH) method (Barrett et al., 1951). 3. Results and discussion 3.1. Drug-free MCC-based pellets In preliminary studies, drug-free MCC-based pellets were prepared using different amounts of water as granulation liquid, i.e., 75, 100 and 110% (w/w) in relation to the MCC weight. The moisture contents are lower than 2% and comparable for all batches regardless of the drying methods, i.e., freeze-drying and oven-drying. The results show that the pellet size is dependent on the amount of granulation liquid and the drying method. Higher amount of granulation liquid results in bigger pellets whereas freeze-drying produces pellets with higher median diameter

Fig. 3. Size distribution determined by sieve analysis on pellet batches granulated with 75% (~,4), 100% (*,) and 110% (^,^) water (in relation to the MCC weight, w/w) and dried by freeze-drying (filled symbol, full line) or oven drying (open symbol, dash line).

(Fig. 3). It has been reported that addition of a larger amount of water produced pellets with larger mass median diameters (Hasznos et al., 1992; Wan et al., 1993; Rough and Wilson, 2005). Water plays the roles of lubricant and plasticizer that facilitate the extrusion of the wet mass. Lower amount of water may produce extrudates with irregular fracture on the surface leading to excessive fragmentation during spheronization and hence produce more fine fractions. In contrast, increasing the amount of water, also acting as a binder, may limit the splitting and/or provoke the agglomeration of extrudates during spheronization. In addition, microcrystalline cellulose described as a “molecular sponge” can absorb large amount of water (Fielden et al., 1988). During the freezing stage of freeze-drying, water absorbed has been converted into ice. The removal of ice crystals by subsequent sublimation creates an open network of “pores” that allows pathways for escape of water vapor. As consequence, the shape and size of the pellets remain nearly unchanged and comparable to those before drying (Song et al., 2007). A slight increase in size can be observed due to the expansion of water when passing from the liquid to the ice state (Bashaiwoldu et al., 2004). In contrast, water evaporation during oven drying occurring in a progressive way leads to wet mass contraction and results in smaller dried pellet size compared to those obtained by freezedrying. According to the European Pharmacopeia, orodispersible dosage forms include drug delivery systems that disintegrate in the patient’s mouth in less than 3 min without the need of water. Specific methods using a texture analyzer to determine the disintegration time of these dosage forms have been described by Dor and Fix (2000) and El-Arini and Clas (2002). This approach presents the advantage of simulating the in vivo realistic conditions where the dosage form is in contact with very small volume of saliva (disintegration medium) and is subjected to some mechanical forces. The technique also allows the precise measurement of a very short disintegration time. In addition, this analytical method is valuable in discriminating between different formulations (El-Arini and Clas, 2002). In this study, the method was validated with regard to the volume of disintegration medium and the applied compression force. There is no significant difference between volumes used ranging from 20 to 100 mL, the minimum value (i.e., 20 mL) was therefore selected. Fig. 4 shows the distance– time curves corresponding to the behavior of freeze-dried pellets when being subjected to the test force (i.e., 50 g). In the absence of water, the pellet resists to the applied force which results in positive distance values. In the presence of water, as the pellet started to disintegrate, the probe has to move further downward in

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3.2. Drug-loaded MCC-based pellets

0.2

distance (mm)

0.1

time (s)

0.0 0

2

4

6

8

10

-0.1 -0.2 -0.3 -0.4 -0.5

Fig. 4. Distance–time profiles of freeze-dried drug-free pellets subjected to compression force (50 g) in the presence of water (full line) and in the absence of water (dash line).

order to maintain the target force, illustrated by the descent of the curve. Table 2 presents the results of disintegration test, with t1 representing the onset point and t2 the endpoint of disintegration process determined from the distance–time curves. Interestingly, the disintegration starts almost immediately as the freeze-dried pellets are in contact with water (t1 approximating to 0) and is entirely completed in a very short period of time (t2 less than 5 s). This is not the case for oven-dried pellets, which do not disintegrate after 60 s and are less suitable for orodispersible solid dosage forms. Indeed if the disintegration time is too long, children will have to keep the pellets in the mouth for at least one minute before swallowing them, which is not feasible. The difference in the disintegration time can be explained by the porous structure of freeze-dried pellets that may facilitate the water uptake by capillary forces and therefore accelerate the disintegration. Otherwise, oven-dried pellets are more compact and less accessible for water uptake. It should be noted that there is no significant difference in disintegration time between pellets prepared with different amount of granulation liquid, which will make it possible the reproducibility of pellet characteristics after industrial production even if the amount of granulation liquid varies. Also, the manufacturing process developed was shown to be able to produce pellets with acceptable quality, e.g., spherical and regular shape (aspect ratio
1), and importantly, having good mechanical properties (low friability) that make them resistant to mechanical stress of further manufacturing processes such as drops, vibration, fluidization, etc, while allowing very fast disintegration.

Table 2 Characteristics of freeze-dried drug-free pellets as a function of the amount of granulation liquid. 75% water

100% water

110% water

Disintegration onset t1 (s) Min 0.00 Max 1.10 Mean  SD 0.22  0.27

0.00 2.74 0.49  0.79

0.00 2.38 0.57  0.67

Disintegration endpoint t2 (s) Min 0.27 Max 1.29 Mean  SD 0.56  0.24

0.26 2.89 0.88  0.74

0.43 3.46 1.19  0.78

Friability (%)

0.24

0.10

0.51

In this section, we examined the feasibility to produce fast disintegrating pellets containing acetaminophen (model drug) by the manufacturing process developed. Freeze-dried MCC-based pellets were prepared at different drug loads, i.e., 25, 50 and 75% (w/w). The amount of granulation liquid was adapted to the content of acetaminophen in order to obtain pellets with acceptable quality. Table 3 summarizes the characteristics of freeze-dried drugloaded pellets, e.g., moisture content, friability, aspect ratio and disintegration properties. The manufacturing process developed was shown to be able to produce high drug loading pellets with acceptable quality, i.e., low friability, good sphericity (aspect ratio
1) and a smooth surface (Fig. 5). Importantly, the pellets exhibit a rapid disintegration as the onset point t1 and the endpoint t2 are approximating to 0 and less than 5 s, respectively. This leads to a rapid drug release that is determined by the dissolution test: more than 90% of drug is released within 15 min for all batches (Fig. 6). The incorporation of acetaminophen did not really delay the disintegration time of the pellets, even with a percentage of 75%. This is promising for the development of very fast disintegrating orodispersible solid dosage forms. Current trends in fast disintegrating drug delivery design consist in the incorporation of superdisintegrant agents and/or the formation of porous structures (Saigal et al., 2008; Parkash et al., 2011). In the latter case, water uptake via the pores is enhanced by capillary forces, which is necessary for disintegration to occur (Faroongsarng and Peck, 1994a). Freeze-drying is the most straightforward technology that allows to obtain a highly porous structure (Schwegman et al., 2005; Liu, 2006). However, the drawback of freeze-drying a solution or suspension is that freeze-dried products are very brittle and difficult to handle due to very large pore size (>10 mm) (Lafon, 1986; Kearney and Wong, 1997; Green and Kearney, 1999; Corveleyn and Remon, 1997). Hence, porous structure has an important role in fast disintegration but also affects the mechanical properties of the dosage form. To characterize the pore structure of freeze-dried pellets containing 25% of acetaminophen, two methods of measurement were used: (i) mercury intrusion technique allows to measure pore size ranging from 0.006 to 250 mm, (ii) smaller pores are only accessible by gas adsorption (Faroongsarng and Peck, 1994a; Bataille et al., 1993; Faroongsarng and Peck, 1994b; Riippi et al., 1998; Vertommen et al., 1998). Fig. 7 shows a plot of pore volume against pore diameter determined by the two mentioned techniques. Pores greater than 100 mm can be attributed to inter-granular spaces between pellets inside the mercury penetrometer. The results obtained by gas adsorption demonstrates a low presence of pores smaller than 0.1 mm whereas mercury intrusion results in higher pore volume value. This may be due to ink-bottle shaped pores and/or interconnected Table 3 Characteristics of freeze-dried drug-loaded pellets as a function of the drug load. 25% drug load

50% drug load

75% drug load

1.00 0.24 1.09

0.40 0.20 1.07

0.51 0.35 1.08

Disintegration onset t1 (s) Min 0.00 Max 0.43 Mean  SD 0.07  0.13

0.00 0.32 0.02  0.14

0.00 0.25 0.03  0.07

Disintegration endpoint t2 (s) Min 0.26 Max 1.54 Mean  SD 0.95  0.42

0.28 1.33 0.85  0.37

0.30 2.08 1.30  0.56

Moisture content (%) Friability (%) Aspect ratio

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Fig. 5. Optical micrographs of freeze-dried drug-loaded pellets.

cumulative release (%)

100

75

25% drug load

50

50% drug load 75% drug load 25

0 10

0

20

30

40

50

time (min) Fig. 6. Dissolution profiles of freeze-dried drug-loaded pellets.

0.12

pores that shift the volume pore size distribution towards smaller pores in mercury intrusion method (Dees and Polderman, 1981). The diameter of the pore opening into the surface of the sample determines when mercury is intruded into the sample. Large pores with a small opening are only filled at high pressure, and therefore detected as smaller pores. In addition, high pressures may cause sample compression especially in samples containing closed pores and hence an apparent uptake of mercury superimposed on the intrusion curve leading to an erroneous indication of pore volume (Johnston et al., 1990; Palmer and Rowe, 1974). Gas adsorption method becomes more appropriate and more relevant to pores with smaller size range, i.e., diameter less than 0.1 mm. Thereby, the internal structure of freeze-dried pellets seems to be characterized mainly by pores with diameter ranging from 0.1 to 10 mm (median pore diameter = 1.19 mm). This pore size allows rapid penetration of the water in the internal structure of the pellets and then their very fast disintegration. These results are in good agreement with SEM analysis. Fig. 8A shows a continuous surface of the freeze-dried pellets, whereas the cross-section images confirms the internal structure of freeze-dried pellets composed of a pore network (Fig. 8B). The characteristics of pore structure indicate the compromise between the fast disintegration of freeze-dried pellets and their mechanical properties. It means that the presence of capillary pores enhances the water uptake and facilitates the disintegration. However, the pore size remains

pore volume (cm3/g)

0.10 0.08 0.06 0.04 0.02 0.00 0.001

0.01

0.1

1 10 pore diameter (µm)

100

1000

Fig. 7. Pore size distribution of freeze-dried drug-loaded pellets determined by gas adsorption technique () and mercury intrusion technique (^).

Fig. 8. SEM micrographs of the surface (A) and the cross-section (B) of freeze-dried drug-loaded pellets (25% drug load).

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