(T1430-03-17) The Sustained Release Potential of MCM-41 versus SBA-16 Serving as Entrapment Carriers after Amine Surface Functionalization

Purpose: Drug loading in amine surface-modified MCM-41 and SBA-16 (mesoporous silica nanoparticles) can occur both on carrier surfaces and inside the pores. A higher percentage of drug can be complexed to internal surfaces of drug carriers than its outside surfaces, and its degree of tortuosity and pore-geometry has the potential to influence its sustained release. A previous study in our lab showed impregnation method using anhydrous alcohol via capillary action on both MCM-41 and SBA-16 was superior to the immersion method in drug loading. This study first investigated water and 0.01 N HCl (simulating fed state gastric fluid) as the in vitro medium to desorb drug from the carrier external surfaces. By doing so, indirect computation entrapment efficiency inside carrier pores may be examined as to whether MCM-41 or SBA-16 has better potential for utilization as an extended-release dosage form in the future. It also aimed to assess loading efficiency using impregnation method for freshly amine surface functionalized carrier group versus those that were functionalized one month ago.

Methods: Amine surface modification was applied to the carrier via the reaction of tetraethylenepentamine (containing primary and secondary amines), 2-amino-2-methyl-1-propanol (containing a primary amine), and anhydrous alcohol. Diclofenac sodium was mixed with amine surface-modified carrier in 1:4 w/w. Due to carrier densities, different volumes of anhydrous alcohol as impregnation medium were required to cover the entire drug-carrier complexation (1.5 mL to MCM-41 while 0.5 mL to SBA-16). After 24-h alcohol evaporation, 5 mL of 0.01 N HCl (simulating fed state gastric fluid) was added to the drug-carrier complex and vacuum filtered immediately to obtain the filtrate containing drug desorbed from the carrier surfaces. Water was used as the control group. The filtrate was quantified using HPLC. The filtered cakes were subject to incubation dried for 1-h at 100°C vs. air-dry for 24-h. Drug entrapment inside the carrier pores was monitored with FTIR. UV spectrophotometer was used to study the effects of longer-term immersion in 0.01 N HCl. The absorbance of diclofenac sodium in the filtrate after 10-min centrifuge and filtered can be used to indirectly find out the drug retained in carriers. After both carriers had been surface modified and stored for one month, the drug load was compared to the freshly prepared group.

Results: There was no significant difference in internal entrapment efficiency between the use of water and 0.01 N HCl as the medium to desorb the drug in MCM-41 or SBA-16. Suggesting 0.01 N HCl did not chemically decompose diclofenac sodium. The use of 0.01 N HCl as an in vitro medium retained more diclofenac in internal pores for MCM-41 than those for SBA-16 (81.1±3.0% vs. 72.3±1.9%, n=3, p < 0.019). The incubation dry method did not affect the drug stability in either carrier. According to the literature the melting point of diclofenac is 156-158℃ but diclofenac sodium is 283-285℃. Air dried samples displayed larger first endothermic peak in the DSC studies. The second endothermic peak in both carriers occurred approximately 205℃ probably due to formation of hydrogen bonds between amines on the surface functionalized carriers with water. As to FTIR, diclofenac sodium has a strong characteristic absorption in the region of 650-900 nm for aromatic C-H bending. A medium strength absorption was recorded in the range of 1550-1650 nm representing aromatic carbon bonds. The fourth spectrum of Figures 1 and 2 which represents drug loaded carriers shows an absence of the strong and medium strength peaks belonging to diclofenac sodium signifying the presence of the drug in carrier. The UV spectra used to assess the longer-term immersion of both drug loaded amine modified carrier only containing drug inside the pores showed the same readings in terms of absorbance wavelength at 275 nm, but the absorbance of SBA-16 was lower in supernatant (p=0.013 < 0.05). In other words, it suggests that diclofenac sodium immersed in 0.01N HCl was entrapped more in SBA-16 than MCM-41. After surface modification to each carrier for one month, the loaded drug amount in each carrier decreased from 78.1±3.5% to 51.8±3.0% in MCM-41; from 67.6±11.5% to 42.9±8.7% in SBA-16 (p < 0.05, Figure 3).

Conclusion: Water and 0.01 N HCl may be used to remove the adsorbed drug on silica carriers. FTIR scans indicated that drug loading did occur in both carriers. Incubation dry showed no negative impact on diclofenac sodium and was a superior method of removing water. Finally, MCM-41 impregnated more diclofenac sodium than SBA-16 utilizing 0.01N HCl but not under longer immersion. Diclofenac sodium release is impacted by the length of the immersion in the simulated fed-state gastric fluid due to the pore structure differences of the carrier. Based on a one-month storage study, drug loading to amine surface-functionalized carriers is recommended immediately to prevent loss of drug loading efficiency.

References: 1. SBA-16. ACS Material. https://www.acsmaterial.com/sba-16.html.
2. Silverstein RM, Webster FX, Kiemle DJ, Bryce DL. Infared Spectrscopy. In: Spectrometeric Identification of Organic Compounds. NJ: Hoboken; Wiley; 2015. p. 80
3. U.S. Pharmacopeial Convention (2022). USP Monographs: Diclofenac Sodium Extended Release Tablets, In: USP43-NF38. Rockville MD: U.S. Pharmacopeia, p. 1350

Figure 1 FTIR scans of SBA-16 and diclofenac sodium. Top spectrum is drug; second spectrum is carriers; third spectrum surface modified carriers; and the bottom spectrum, drug loaded in surface modified carriers.



Figure 2 FTIR scans of MCM-41 and diclofenac sodium. Top spectrum is drug; second spectrum is carriers; third spectrum surface modified carriers; and the bottom spectrum, drug loaded in surface modified carriers.



Figure 3 Entrapment efficiency of carriers after one month storage after air dry. Data suggests that entrapment after 1 month significantly reduced drug loading.