development and standardization of capsules and …

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aLaboratório de Pesquisa em Fármacos, Departamento de Ciências Biológicas e da Saúde, Colegiado de Farmácia, Universidade Federal do Amapá,bPrograma de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmacia, Universidade Federaldo Pará, cLaboratório de Nanobiotecnologia Fitofarmaceutica, Departamento de Ciências Biológicas e da Saúde, Co-legiado de Farmácia, Universidade Federal do Amapá,dFacultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, México D.F., México*Correspondence: J. C. T. Carvalho, Laboratório de Pesquisa em Fármacos, Departamento de CiênciasBiológicas e da Saúde, Universidade Federal do Amapá, 68902-280 - Rod.. JK, km 2 – Macapá, AP, Brasil. Email: [email protected]

DEVELOPMENT AND STANDARDIZATION OF CAPSULES AND TABLETS CONTAINING L.HYDROETHANOLIC EXTRACT

HELISON DE OLIVEIRA CA ARVALHOa, LARISSA DANIELE MACHADO GÓESa, NÁDIA MA ARIA BA ARBOSA CA UNHAa,b, ADRIANA MA ACIEL FERREIRAa, CAIO PINHO FERNANDESc, HUGO ALEXANDRE SILVA FA AVACHOa, JOSÉ OTAVIO CARRERA SILVA JA UNIORb , BRENDA LORENA SÁNCHEZ ORTIZa,d, ANDRÉS NAVARRETEd, JOSÉ CARLOS TAVARES CARVALHOa,b*

ABSTRACT

Due to the importance of L. as a medicinal plant extensively used in traditional medicine around the world, this study aimed to develop andstandardize solid pharmaceutical forms (capsules and tablets) from granulated containing L. hydroethanolic extract (CoHEE), and outline

showed a mix of homogeneous granules of irregular and semi-spherical surfaces, with a predominance of sizes of 180-250 uM from 10 to 37%. The quality control of pharmaceutical forms, as the average weight, disintegration test, hardness and

-

both dissolution media, hydrochloric acid buffer and distilled water. The distilled

of 7.64 % (0.0013 mg/mL) for tablets. The hydrochloric acid buffer medium showed

is concluded that the methods employed to obtain the granulated with further achievement of capsules and tablets were effective for maintain a standard of

phytochemical-drug marker, and a possible standard pharmacological effect in

Keywords: L., Capsule and tablet, Quality control, Granulated, Flavonoids, Dissolution test.

INTRODUCTION

The use of herbal medicine products hasgrown in the therapy and its importance is highlighted in the recent years, and this is

of the therapeutic properties of plants and the development of new formulations at low cost, making the society increasingly valorize such products (Melo et al., 2007).

The current trend is to require from thedevelopment of herbal medicine a strictquality control as well as the is from requi-red synthetic drugs. For this to occur, theplants must be in standard forms with thequalitative and quantitative characteriza-tion of its active principles, providing the requirements of quality, effectiveness and safety, which are needful in a modern phar-maceutical preparation (Souza-Moreira et al., 2010).

Herbal medicine result from the proces-sing stages of vegetal raw material, and the quality of the product is the result of thequality of each step starting with the origin of the plant and post-harvest care until its transformation into a pharmaceutical raw material (Couto et al., 2001).

In relation to the obtain pharmaceutical forms derived from vegetable raw material, in addition to the initial planning to ma-nipulate the vegetable raw material, the standardization of the herbal medicine is

product is guaranteed with the constancy of the content of principles, through theapplication of suitable analytical methods

-mical markers, in order to obtain a material suitable for consumption, guaranteeing its biological action and safety (Carvalho et al., 2008).

RESUMEN

Debido a la importancia de L. como una planta medicinal ex-tensamente utilizada en la medicina tradicional alrededor del mundo, el objetivo de este estudio fue desarrollar y estandarizar formas farmacéuticas sólidas (cápsulas y tabletas) de granulado que contengan el extracto hidroetanolico de Calendula

por Microscopia electrónica de barrido (MEB) mostraron una mezcla de gránulos

de 180-250 uM de 10 a 37%. El control de calidad de las formas farmacéuticas,como: el peso medio, prueba de desintegración, dureza y grosor, fue satisfactorio

de las cápsulas y tabletas fueron efectivos en ambos medios de disolución, tampón

mL) para las tabletas y el medio tampón de ácido clorhídrico mostro la liberación -

cluye que los métodos emplean para el granulado en cápsulas y tabletas, fueron

Palabras clave: L., Capsula y tableta, Control de calidad,Granulado, Flavonoides, Prueba de Disolución.

Development and standardization of capsules and tablets containing L. /1 (2018) 17

18 H. DE OLIVEIRA CA ARVALHO, ET AL.

Calendula ( L.) is popularly known in Brazil as “maravilha”, “bem-me-quer”, “margarida dourada”. The

topical preparations for the treatment of sunburn, burns and dry dermatosis, as anti-inflammatory and wound healing,whose properties have been proven expe-rimentally and attributed in large part to

et al., 2005). Calendula

components: essential oils, salicylic acid,-

terpenic saponins. Flavonoids are chemical markers, and among them, quercetin 3-O-rutinoside, or rutin, is highlighted (Souza et al., 2010).

The aim of this study was to develope and standardize capsules and tablets from

L. hydroethanolic ex-tract (CoHEE) and evaluate the dissolution

marker of pharmaceutical forms.

MATERIAL AND METHODS

Obtainment of plant material and of CoHEEL.

were used and acquired from Florien Co. (Lot: 046 062, Piracicaba-SP-Brazil). To

were submitted to maceration in 70% hy-droethanol solution at a controlled tempe-rature of 45°C for 7 days in a ratio of 1:8

rotaevaporator (Quimis, Model 218.2 Q) at a temperature of 50°C until complete evaporation of the solvent.

Physical and chemical standardizationof CoHEEPhysical standardization of CoHEE wasrealized based on the determination of pH,

were performed in triplicate according methodologies described by the Brazilian

Pharmacopoeia (2010). The chemical stan-dardization of CoHEE was related to the

by spectrophotometry based on the reac-tion with aluminum chloride (AlCl3) 2%, as described by the Brazilian Pharmacopoeia (2010) and by the spectroscopic characte-rization in the infrared region. The spectra infrared transformed into Fourier (FT-IR) of the CoHEE were obtained on Shimadzu spectrometer, FTIR-8400S model, opera-ting in Fourier transformer. The spectra were obtained in the region of 4.500 to 500 cm-1 using KBr pellets (solid samples) with4.0 resolution and 64 scans.

Obtainment of granulated CoHEE The granulated CoHEE was obtained from the manual mixing of concentrated extract and excipients in the following proportion: 31.92% of CoHEE, 33.35% of D-lactosemonohydrate Vetec® (Vetec Fine Chemi-cals Ltd., Rio de Janeiro, Brazil), 21.80% of Avicel® cellulose (Sigma. - Aldrich Co.,St. Louis, USA), 9.06% of Duryea starch,3.87% of magnesium stearate RiedeldeHaen® (Sigma - Aldrich Co., St. Louis, USA.). The obtained mass was granulated in nº 25 sieve with mesh width of 0.71 mm. The granules obtained were taken in drying kilns at 35°C. After drying, the gra-nulate was passed again through sieves, with the purpose of homogenizing (Rocha et al., 2009).

Determination of granulated characteristics by Scanning Electron Microscopy For the analysis of scanning electron mi-croscopy (SEM), the samples of the gra-nulated were previously metallized in a

in metallic holder and then analyzed in a scanning electron microscope (SEM-Joel JSM 6060). They evaluated the morpho-logy, homogeneity and surface size of the granules according to the method described by Costa et al. (2006).


Obtainment capsules and tablets fromgranulated CoHEECapsules were obtained through manualencapsulation of the granulate into hard gelatin capsules of size 00. The tablets wereobtained by compression of the granulatedin a manual Shimadzu compressor with 20 KN compression force for 4 minutes.

Determination of CoHEE content contained in the dosage formsThe amount of CoHEE contained in each capsule and tablet was determined from theobtained average of the respective weights using the equation described by Carvalho et al., (2013).

Where: Tec = extract contained in

granules (g).

Average weightThe methodology provided by the Brazilian Pharmacopoeia (2010) was applied with an individual analysis of 20 units of pharma-ceutical forms, with ± 7.5% of tolerance

-rating no more than two units outside that

Disintegration testThe disintegration test was conducted in a disintegrator equipment model 301 /3AC (New Ethics, Ltda. Sao Paulo, Brazil), containing three baskets. It was used 06 units of pharmaceutical forms by placing them in each of the six tubes of the basket, employing as immersion médium: distilled water, hydrochloric acid buffer (pH 1.2) and phosphate buffer (pH 6.8) at a temperature of 37 ± 1°C. For capsules, the maximum acceptance disintegration time was 45 mi-nutes and 30 minutes for tablets (Brazilian Pharmacopoeia, 2010).

The dissolution test was performed ac-

cording to the conditions described in theBrazilian Pharmacopoeia (2010), for the test is was used a dissolutor equipmentwith six tanks, model 299 (New Ethics, Ltda. Sao Paulo, Brazil) employing as dis-solution medium: 900 mL of hydrochloric

maintained with a medium at 37.0 ± 1°Cand as apparatus, basket for capsules and tablets paddle. The test was performedwith 6 units of each pharmaceutical formin each dissolution medium. The release

quantization of pharmaceutical forms dis-solved in dissolving baskets on 5, 10, 15, 25, 40 and 60 min. Aliquots of 5 mL were centrifuged for 2 minutes at a speed of 3200 rpm, 3 mL of the supernatant were used todetermine the rutin concentration by spec-trophotometry in the ultraviolet region in a spectrophotometer UV-mini model 1240 (Shimadzu Corporation, Kyoto, Japan) at a wavelength of 425 nm.

Thickness and hardness of the tabletsTo the thickness test, it was used a caliper (Zaas Precision) to determine the thickness of 10 tablets. The result was expressed as the mean values obtained in the deter-minations. For the hardness test, it was used a durometer (New Ethics Ltda. Sao Paulo, Brazil). 10 tablets were subjected to a force required to crush or break under radial pressure. The force was measured in Newtons (N), and the result was expressed as the mean values obtained in determina-tions (Brazilian Pharmacopeia, 2010).

Statistical analysisIn order to know if tablets and capsules differed in acid medium and in distilled water, it was use d the Student’s T test. The assumptions of homoscedasticity and normality of the data were evaluated by F test (variance ratio) and Shapiro Wilk respectively.


RESULTS AND DISCUSSION

The solid pharmaceutical forms orally ad-ministered are favored by several factors such as ease of administration, convenien-ce and safety. In the case of pharmaceu-tical products from vegetable, because of its chemical complexity, the pharmacistsprofessionals looks for the handling of pro-ducts containing standardized and quality extracts, since only in this way they canbe sure of the concentration of the active substances and the availability of these inthe body.

The CoHEE presented pH 5.8, being considered an acid extract. The pH of anextraction solution provides information regarding the stability and character of the molecules present in the preparation. The dry residue obtained for CoHEE was1.7% and the calculations made to arrive at a soft CoHEE mass for use in granular preparation was based on these results. The relative density was 0.89067 g/mL. The dry residue and the relative density are important parameters for controlling the extraction process of medicinal plants,providing the basis for extractive yield cal-culation. In general, values for the residueand density for dyes range from 1 to 6%and 0.87-0.98 g/mL, respectively, and the-se values may vary with the plant species (Prista et al., 1996).

The determination of the dry residue is a fundamental and primary parameter

herbal formulation, because it involves the

the plant by removing the extractor solvent (Oliveira and Berretta, 2007).

The chemical standardization of CoHEE was realized by quantifying the content of

the CoHEE presented 1.36% of content

of L., spectroscopy technique was used in the region infra-red, which aims to identify determine the

characteristic functional groups of marker-

liminary study of its chemical structures (Maciel et al., 2002).

The absorption spectrum of rutin che-mical marker showed characteristic ab-sorption bands of the functional groups of the chemical structure. A broad absorption band at 3361 cm-1 was attributed to the stretching of the phenolic hydroxyl, andthe absorption band at about 2937 cm-1

can be linked to axial deformation of the C-H of aromatics. According to Jin et al.(2007), the absorption band at 1654 cm-1, presented in the rutin spectrum is attri-buted to the stretching of the carbonyl (C

-1, 1508 cm-1

and 1458 cm-1 are for the stretching of thephenyl ring (C = C). The absorption band around 1296 cm-1 was attributed to stret-ching C = C-O-C and the absorption band at 1203 cm-1 can be related to the angulardeformation of the C-H connection plane of the aromatic ring (Silverstein, et al., 2006) (Figure 1).

Figure 1 shows the spectrum in the

absorptions at 3373-2927 cm-1 with strong intense are originated from asymmetric

as OH) of the link and sym-as CH2). The intense absorption

at 1616 cm-1 refers to carbonyl group (C = O). The signal at 1458 cm-1 can be assignedto the symmetric angular deformation in the plane of the methylene group. In 1400cm-1 appears with a mean intensity and itis related to the symmetric angular defor-mation of the methyl group of -CH (CH3)(Table I). In 1056 cm-1 shows a broad signal and relatively Strong, characteristic of the axial deformation of the functional group (C - O - C) (Silverstein et al., 2006).

In the development of the granulated CoHEE the following excipients were used (Table II): microcrystalline cellulose and monohydrate lactose, as diluents in the for-


-rate as a lubricant to reduce friction during tablet compression process and starch, which besides aggregating function, acts as disintegrant, promoting disintegration of solid particles into smaller, more easily dispersable or soluble.

From this formulation, it was obtained a granulated with yellow color, characteristicodor of the plant species and through scan-ning electron microscopy, it was possible

with granulated having a size predominan-ce of 180-250 uM with percentages from 10 to 37% (Figure 2), it was also possible to observe granulated with irregular surfaces

b a

Figure 1.-

cinalis L. hydroethanolic extract (CoHEE) (b).

Table 1. Absorption bands in the infrared region,

Absorption bands Vibration Characteristics(cm-1)

1616 C = O1458 C = C1400 C = C1056 (C – O – C)

Table 2. Percentage and mass of the granulated -

droethanolic extract (CoHEE)

Granulated Mass (g) Percentage

Microcrystalline cellulose 36,12 21,8 %Magnesium stearate 6,39 3,87 %D-lactose monohydrate 55,26 33,35 %Starch 15 9,06 %CoHEE 52,80 31,92 %Total 165,57 100%

130 165 180 195 215 250 2900

25

50

75

100

Size (μm)

Perc

enta

ge

Figure 2. Presents the variation in size of the granu-lated from CoHEE measured by Scanning Electron Microscopy (SEM). Photomicroscopies obtained by Scanning Electron Microscopy (SEM) of the granulatefrom CoHEE presented in: A) forms with irregularsurface, B) semi-spherical grain structure, C) and D) homogeneous granules in the size range of 500 and 700 uM, respectively.


and with semi-spherical agglomeration of the constituent particles (Figure 3). These characteristics are essential to obtain a good disintegration and dissolution, since these agglomerated particles, when hydra-ted, they exhibit easy separation.

The capsules and manipulated tablets were subjected to quality control tests, which were: average weight, hardness and thickness (for tablets), disintegration anddissolution, which consists of a set of ope-rations in order to verify that the product is in accordance with the pharmacopoeia

pharmacist ensures product quality, safe-et al.,

2005).

According to Ansel et al. (2000), tabletsshould have physical and chemical stabi-lity, disintegrate on time, be a little crispy, display integrity and smooth, bright and

and contamination. They may also be va-ried among themselves in relation to thethickness, diameter, size, weight, shape, hardness, disintegration characteristicsdepending on the manufacturing methodand the purpose of use.

CoHEE tablets had a thickness of 3.00 mm and hardness of 34.3 N. The Brazilian

-nimal hardness acceptable for tablets of 30 N, thus, the tablets analyzed showed an appropriate resistance to abrasions andmechanical shock. The determination of average weight informs homogeneity per lot unit and establishes an essential toolfor quality control, which may indicate in-

et al., 2012). According to the Brazilian Pharmacopoeia (2010) the range of accep-table weight for each tablet with an averageweight above 250 mg is ± 5.0%, not being allowed more than two units outside the

tablets were used to determine the average-

(Table III) and from the formula describedby Carvalho et al. (2013), it was possible to achieved the average content of CoHEE inthe tablets averaging 0.149 ± 0.002.

The average weight for CoHEE capsules was 549 mg, and to this pharmaceutical

Figure 3.granulated CoHEE in the dissolution medium, dis-tilled water (DW) and hydrochloric acid buffer (AT).

Table 3. Determination of the average weight of pharmaceutical forms, hardness and thickness of theCoHEE tablets

Pharmaceuticalform

Average weight (g)

Higherweight found

(g)

Smallerweight found

(g)

RSD (%) Hardness(N)

Thickness(mm)

Capsules 0,549 0,557 0,543 4,47% - -

Tablets 0,551 0,557 0,544 4,18% 34,3 3,00

RSD – Relative Standard Deviation


form, Brazilian Pharmacopoeia (2010) re-commends that for each capsule with an average weight of 300 mg the above varia-tion range is ± 7.5% not being allowed more

in this test all capsules analyzed showedsatisfactory results within the upper and lower limits (Table III), and the average content of CoHEE in capsules was 0.149± 0.005.

According to Peixoto et al., (2005),the determination and adjustment of theweights of pharmaceutical forms during the production process are important procedu-res, since the formulas are based on theweight of the pharmaceutical forms, which

active ingredients in each unit, in the re-sults of the average content of CoHEE of pharmaceutical forms, and it was observed that both capsules and tablets showed uni-formity of content, which is directly relatedto middleweight.

The disintegration of tablets and capsu-les directly affects absorption, bioavailabi-lity and therapeutic drug action. In order to the active ingredient be available to be absorbed and exerts its pharmacological action, it needs to occur disintegration of the solid dosage form into small particles,increasing the surface of contact with the dissolution medium, favoring, therefore, its absorption and bioavailability in the body (Peixoto et al., 2005).

The disintegration test checks whether tablets and capsules disintegrate within

-dia, and Brazilian Pharmacopoeia (2010)

stipulates that after 30 minutes the un-coated tablets must be disintegrated and

minutes. The CoHEE capsules disinte-grated in a shorter time compared to thetablets, and the maximum disintegrationtime for the capsules was 11 minutes in distilled water and in acidic buffer (pH 1.2)

the tablets have disintegrated in a shortertime in phosphate buffer (pH 6.8) with 12

characterizing this longer disintegrationtime for the tablets (Table IV).

The variation in disintegration of cap-sules and tablets vary, as the capsuleshell dissolves in the dissolution medium, releases the granulated which immedia-tely begins to solubilize the dissolution medium, since the tablets being subjected to a compressive force maintains the co-hesive beads, which took a longer time to disintegrate. In this study, both capsules and tablets disintegrated within the limits

(2010).With the development of technology and

research involving the release of drugs, thedissolution test has emerged as an indica-tor for assessing the quality of solid dosageforms for oral use and it is used both for thequality control of medicines and as a guidein developing new formulations and espe-cially in preliminary bioavailability studies.

The absorption of drugs from solid phar-maceutical forms depends on: the releaseof the same pharmaceutical form, their dissolution or solubility under physiological

Table 4. Disintegration Time (min) of CoHEE capsules and CoHEE tablets in different disintegration medium (n = 6).

Dissolution medium Disintegration time of tablets (min)

Disintegration time of capsules (min)

Distilled water 13 11

Hydrochloric acid buffer (pH 1.2) 14 4

Phosphate buffer (pH 6.8) 12 8


conditions and their permeability throughthe gastrointestinal tract. Thus, modelsthat can predict the absorption of drugs from the dissolution studies are limited by the complexity of the phenomena occu-rring at gastrointestinal tract (Malesuik et al., 2006). Thus, for the dissolution test to predict the performance, it has to be used a dissolution medium that simulate physiological conditions (Cardoso et al., 2007). The study of dissolution of CoHEE capsules and tablets it was used as disso-lution medium the distilled water and the buffer solutions (acid and phosphate withpH 1.2 and 6.8, respectively).

capsules was conducted at three differentimmersion media: distilled water, hydro-chloric acid buffer (pH 1.2) and phosphatebuffer (pH 6.8), the later one was not possi-

-vonoids on pharmaceutical forms, because before the absorbance in a spectrophoto-meter reading, the samples were subjected to the reaction with AlCl3 2% in and aceticacid 5% in methanol to be analyzed after 30 min, in a spectrophotometer at 425 nm. In this reaction, in phosphate buffer (pH 6.8) it was observed a complex that masked the absorbance readings, invalidating the testwhen using this buffer.

The dissolution test for CoHEE tablets showed better performance in distilled water, in 15 min showed a release of 5.2%

increasing as function of time, and at the end of the dissolving assay, in 60 min the

-noids release has been reduced in relation to the distilled water in 15 min release of

dissolution test (Figure 3).The dissolution test for CoHEE capsu-

les also showed better performance in the

concentration dissolved in medium was

increasing gradually as a function of time

-

medium in distilled water, because there was a gradual increase in the concentration

of time, and the release in the end of the dissolution test was 4.7% (0.0008 mg/mL)

tablets in distilled water were similar, at-

dissolution test, but for tablets in the last-

ds was 7.64% (0.0013 mg/mL), featuring -

ved in the study. In the hydrochloric acid buffer medium, the pharmaceutical forms also showed similar behavior, in respect

CoHEE capsules presented smaller valuesof concentration. In 15 minutes, the per-

(0.0005 mg/mL) for capsules and 2.29% (0.00039 mg/mL) for the CoHEE tablets,

Figure 4.granulated CoHEE in the dissolution medium, dis-tilled water (DW) and hydrochloric acid buffer (AT). (t = -3.7478, df = 67.838, p> 0.001).


and at the end of dissolution testing, the

acidic medium, was 4.94% (0.00084 mg/mL) for capsules and 3.05% (0.00052 mg/mL) for tablets (Figure 5).

The dissolution of pharmaceutical forms (CoHEE capsules and tablets) of

L. is related to its chemical tracer (rutin) bioavailability inthe body. Therefore, it is essential that the solid pharmaceutical forms of Calendulabe dissolved, releasing a certain percentage

in order to become available to exert its therapeutic action.

The distilled water medium showed the

and tablets, according Zuanazzi et al.,(2002), heterosides are generally soluble in water and diluted alcohols, and this is theadvantageous feature for -

and tablets in hydrochloric acid buffer andin distilled water showed effective disso-lution percentage results, which can berelated to their performance .

CONCLUSION

Through physicochemical characterization of hydroethanolic extract of -

L. it was possible to obtain pharma-

established for quality criteria described in the Brazilian Pharmacopoeia (2010) and

Therefore, it is concluded that the methods employed for CoHEE obtention and granulation with subsequent achieve-ment of capsules and tablets were effective

-se of the appropriate phytochemical-drug marker, and a possible standard phar-

reproducibility.

ACKNOWLEDGMENT

We thank the Brazilian Federal Agency for Support and Evaluation of Graduate Edu-cation (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES) for the grant bestowed, and CNPq Process number 407768/2013-0 (Rede Amazonica de Pesquisa em Biofarmacos – RAPBioFar).

DECLARATION OF INTEREST

Figure 5.tablets and capsules containing granulate CoHEE, wherein: a) distilled water (tablets), B) distilled water (capsules) c) Hydrochloric Acid (capsules), D) hydro-chloric acid (tablets) . (F [3, 136] = 20,084, p> 0.001)

REFERENCES

Ansel, H.C., Popovich, N.G., Allen, J.R.L.V. (2000). Farmacotécnica: formas farmacêuticas & sistemas de liberação de fármacos. São Paulo: Premier.


Brum, T.F., Laporta, L.V., Pons, J.R., Gonçalves, C.A., Santos, M.R. (2012). Equivalência

contendo paracetamol. Rev Ciênc Farm Básica Apl. 33:373-378.Cardoso, S.G., Bajerski, L., Malesuik, M.D., Dorfey, B. (2007). Desenvolvimento de Método de

Dissolução e Estudo comparativo de Formas Farmacêuticas Sólidas contendo cetrizina.26,108-114.

Carvalho, A.C.B., Balbino, E.E., Maciel, A., Perfeito, J.P.S. (2008). Situação do registro de 18, 314–319.

Carvalho, H.O., Medeiros, B.J.L., Sá, B.M., Araújo, J.T.C., Kawakami, M.Y.M., Favacho, H.

containing the dried hydroethanolic extraxct of -

Costa, A.C.F.M., Vilar, M.A., Lira, H.L., Kiminami, R.H.G.A., Gama, L. (2006) Synthesis andcharacterization of TiO2 nanoparticles. , 52, 255-259.

Couto, A.G., Bassani, V.L., Ortega, G.G., Petrovick, P.R. (2001). Caracterização tecnológica do produto seco por aspersão de L. (Euphorbiaceae). 20, 189–196.

Farmacopéia Brasileira. 5 ed. Volume 1. Agência Nacional de Vigilância Sanitária. Brasília: Anvisa. 2010.

Malesuik, M.D., Cardoso, S.G., Lanzanova, F.A., Bajerski, L., Dorigoni, E. (2006). Desenvolvi-mento de teste de dissolução e estudo comparativo de comprimidos e cápsulas magistrais contendo anlodipino. . 27, 37-49.

Maciel, M.A.M., Pinto, A.C., Veiga Jr, V.F. (2002). Plantas medicinais: a necessidade de estudo multidisciplinares. , 25, 429-438.

Melo, J.G., Martins, J.D.G.R., Amorim, E.L.C., Albuquerque, U.P. (2007). Qualidade de produ-tos a base de plantas medicinais comercializados no Brasil: castanha-da-índia (

L.), capim-limão ( (DC.) Stapf ) e centela (Centella (L.) Urban). 21, 27-36.

Oliveira, A.H., Berretta. A.A. (2007). Avaliação da qualidade de insumos farmacêuticos a base de Calêndula e Própolis utilizados pelas farmácias magistrais. -

, 4, 196-174.Peixoto, M.M., Santos Jr, A.F., Santos, C.A.A., Caetité Jr, E. (2005). Avaliação da qualidade

de comprimidos de captopril dispensados em Feira de Santana – BA. , 16, 13-14.Prista, L.N., Alves, A.C., Morgado, R.. Tecnologia farmacêutica. 4 ed., Lisboa: Fundação Ca-

louste Gulbenkian, 1996.Rocha, A.P.T., Silva, V.S., Silva, O.S., Alsina, O.L.S. (2009). Caracterização física de grânulos

de quebra- pedra para uso em leito de jorro. , 4, 32-37.Rolim, A., Maciel, C.P.M., Kaneko, T.M., Consiglieri, V.O., Salgado Santos, I.M.N., Velasco, M.V.

Adr. Juss (Meliaceae) and 133 Bentham (Olacaceae) Commercial Extract. . 88, 1015-1019.

orgânicos. 7a ed., Editora: LTC, 86-87. Souza, A.P.T.B., Barni, S.T., Ferreira, R.A., Couto, A.G. (2010). Desenvolvimento tecnológico

L. empregando planejamento fatorial. 29, 13-21.

Souza-Moreira, T.M., Salgado, H.R.N., Pietro, R.C.L.R. (2010). O Brasil no contexto de controle de qualidade de plantas medicinais. 20, 435-440.


Zuanazzi, J.A.S. Flavonóides. In: Simões, C.M.O., Schenkel, E.P., Gosman, G., Mello, J.C.P., Mentz, L.A., Petrovick, P.R.. Farmacognosia: da planta ao medicamento. 4° ed. Porto Ale-gre: UFSC, p. 197- 220. 2004.

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